Mohab M Ibrahim

Interests

Research

Pre clinical and clinical research investigating both pharmacological and non pharmacological methods to manage chronic and cancer pain

Teaching

Mentoring fellows and residents

Courses

Scholarly Contributions

Books

• Ibrahim, M. M. (2016). Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Elsevier.
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  The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen orNSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have beenidentified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine andethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including rewardliability. We determined if analgesic synergy exists between the mu-opioid agonist morphine and theselective CB2 agonist, JWH015, in rodent models of acute and chronic inflammatory, post-operative, andneuropathic pain using isobolographic analysis. We also investigated if the MOR-CB2 agonist combinationdecreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinaltransit. Co-administration of morphine with JWH015 synergistically inhibited preclinical inflammatory,post-operative and neuropathic-pain in a dose- and time-dependent manner; no synergy was observedfor nociceptive pain. Opioid-induced side effects of impaired gastrointestinal transit and CPP weresignificantly reduced in the presence of JWH015. Here we show that MOR þ CB2 agonism results in asignificant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwantedside effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancementof a MOR-CB2 agonist combinatorial pain therapy for clinical trials.
• Ibrahim, M. M. (2015). Essential Clinical Anesthesia Review: Keywords, Questions and Answers for Boards.
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  1. Ibrahim, Mohab, Aglio, Linda: “Abdominal aneurysm” book chapter in “Essential Clinical Anesthesia Review: Keywords, Questions and Answers for Boards”, Cambridge University Press, United Kingdom, April 2015

Journals/Publications

• Agari, T., Ahmed, S., Andrés Ares, J. D., Assil, K., Atallah, J., Berg, A. P., Bhatia, S., Bojrab, L., Brennan, J. J., Brill, S., Bujedo, B. M., Buwembo, J., Calodney, A. K., Candido, K. D., Carnes, P., Carolis, G. D., Chandler, B., Cid, J., Coster, O. D., , Crooks, M. T., et al. (2023).

  Long-term safety of spinal cord stimulation systems in a prospective, global registry of patients with chronic pain

  . Pain Management, 13(2), 115-127. doi:10.2217/pmt-2022-0091
• Banik, R. K., Sia, T., Ibrahim, M. M., Sivanesan, E., Uhelski, M., Pena, A., Streicher, J. M., & Simone, D. A. (2023). Increases in local skin temperature correlate with spontaneous foot lifting and heat hyperalgesia in both incisional inflammatory models of pain. Pain reports, 8(5), e1097.
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  This study investigated if a localized increase in skin temperature in rat models of incisional and inflammatory pain correlates with the intensity of spontaneous and evoked pain behaviors.
• De La Rosa, J. S., Brady, B. R., Ibrahim, M. M., Herder, K. E., Wallace, J. S., Padilla, A. R., & Vanderah, T. W. (2023). Co-occurrence of chronic pain and anxiety/depression symptoms in U.S. adults: prevalence, functional impacts, and opportunities. Pain.
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  Co-occurrence of chronic pain and clinically significant symptoms of anxiety and/or depression is regularly noted in the literature. Yet, little is known empirically about population prevalence of co-occurring symptoms, nor whether people with co-occurring symptoms constitute a distinct subpopulation within US adults living with chronic pain or US adults living with anxiety and/or depression symptoms (A/D). To address this gap, this study analyzes data from the 2019 National Health Interview Survey, a representative annual survey of self-reported health status and treatment use in the United States (n = 31,997). Approximately 12 million US adults, or 4.9% of the adult population, have co-occurring chronic pain and A/D symptoms. Unremitted A/D symptoms co-occurred in 23.9% of US adults with chronic pain, compared with an A/D prevalence of 4.9% among those without chronic pain. Conversely, chronic pain co-occurred in the majority (55.6%) of US adults with unremitted A/D symptoms, compared with a chronic pain prevalence of 17.1% among those without A/D symptoms. The likelihood of experiencing functional limitations in daily life was highest among those experiencing co-occurring symptoms, compared with those experiencing chronic pain alone or A/D symptoms alone. Among those with co-occurring symptoms, 69.4% reported that work was limited due to a health problem, 43.7% reported difficulty doing errands alone, and 55.7% reported difficulty participating in social activities. These data point to the need for targeted investment in improving functional outcomes for the nearly 1 in 20 US adults living with co-occurring chronic pain and clinically significant A/D symptoms.
• Deer, T., Gilligan, C., Falowski, S., Desai, M., Pilitsis, J., Jameson, J., Moeschler, S., Heros, R., Tavel, E., Christopher, A., Patterson, D., Wahezi, S., Weisbein, J., Antony, A., Funk, R., Ibrahim, M., Lim, C., Wilson, D., Fishell, M., , Scarfo, K., et al. (2023). Treatment of Refractory Low Back Pain Using Passive Recharge Burst in Patients Without Options for Corrective Surgery: Findings and Results From the DISTINCT Study, a Prospective Randomized Multicenter Controlled Trial. Neuromodulation : journal of the International Neuromodulation Society, 26(7), 1387-1399.
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  Spinal cord stimulation (SCS) is effective for relieving chronic intractable pain conditions. The Dorsal spInal cord STImulatioN vs mediCal management for the Treatment of low back pain study evaluates the effectiveness of SCS compared with conventional medical management (CMM) in the treatment of chronic low back pain in patients who had not undergone and were not candidates for lumbar spine surgery.
• Ibrahim, M. M. (2023).

  Co-occurrence of chronic pain and anxiety/depression symptoms in U.S. adults: prevalence, functional impacts, and opportunities

  . Pain. doi:10.1097/j.pain.0000000000003056
• Ibrahim, M. M. (2023).

  Increases in local skin temperature correlate with spontaneous foot lifting and heat hyperalgesia in both incisional inflammatory models of pain

  . PAIN Reports, 8(5), e1097. doi:10.1097/pr9.0000000000001097
• Stratton, H. J., Boinon, L., Gomez, K., Martin, L., Duran, P., Ran, D., Zhou, Y., Luo, S., Perez-Miller, S., Patek, M., Ibrahim, M. M., Patwardhan, A., Moutal, A., & Khanna, R. (2023). Targeting the vascular endothelial growth factor A/neuropilin 1 axis for relief of neuropathic pain. Pain, 164(7), 1473-1488.
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  Vascular endothelial growth factor A (VEGF-A) is a pronociceptive factor that causes neuronal sensitization and pain. We reported that blocking the interaction between the membrane receptor neuropilin 1 (NRP1) and VEGF-A-blocked VEGF-A-mediated sensory neuron hyperexcitability and reduced mechanical hypersensitivity in a rodent chronic neuropathic pain model. These findings identified the NRP1-VEGF-A signaling axis for therapeutic targeting of chronic pain. In an in-silico screening of approximately 480 K small molecules binding to the extracellular b1b2 pocket of NRP1, we identified 9 chemical series, with 6 compounds disrupting VEGF-A binding to NRP1. The small molecule with greatest efficacy, 4'-methyl-2'-morpholino-2-(phenylamino)-[4,5'-bipyrimidin]-6(1H)-one, designated NRP1-4, was selected for further evaluation. In cultured primary sensory neurons, VEGF-A enhanced excitability and decreased firing threshold, which was blocked by NRP1-4. In addition, NaV1.7 and CaV2.2 currents and membrane expression were potentiated by treatment with VEGF-A, and this potentiation was blocked by NRP1-4 cotreatment. Neuropilin 1-4 reduced VEGF-A-mediated increases in the frequency and amplitude of spontaneous excitatory postsynaptic currents in dorsal horn of the spinal cord. Neuropilin 1-4 did not bind to more than 300 G-protein-coupled receptors and receptors including human opioids receptors, indicating a favorable safety profile. In rats with spared nerve injury-induced neuropathic pain, intrathecal administration of NRP1-4 significantly attenuated mechanical allodynia. Intravenous treatment with NRP1-4 reversed both mechanical allodynia and thermal hyperalgesia in rats with L5/L6 spinal nerve ligation-induced neuropathic pain. Collectively, our findings show that NRP1-4 is a first-in-class compound targeting the NRP1-VEGF-A signaling axis to control voltage-gated ion channel function, neuronal excitability, and synaptic activity that curb chronic pain.
• Calligaro, H., Cheng, K., Ibrahim, M. M., Martin, L. F., & Patwardhan, A. (2022).

  Case Report: Green Light Exposure Relieves Chronic Headache Pain in a Colorblind Patient

  . Clinical Medicine Insights: Case Reports, 15, 117954762211251. doi:10.1177/11795476221125164
• Cheng, K., Flowers, M. E., Ibrahim, M. M., Korah, H. E., Martin, L. F., Patwardhan, A., Stratton, H. J., & Washington, S. M. (2022).

  Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies

  . Journal of Visualized Experiments. doi:10.3791/64555
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  Management of chronic pain remains challenging to this day, and current treatments are associated with adverse effects, including tolerance and addiction. Chronic neuropathic pain results from lesions or diseases in the somatosensory system. To investigate potential therapies with reduced side effects, animal pain models are the gold standard in preclinical studies. Therefore, well-characterized and well-described models are crucial for the development and validation of innovative therapies. Partial ligation of the sciatic nerve (pSNL) is a procedure that induces chronic neuropathic pain in mice, characterized by mechanical and thermal hypersensitivity, ongoing pain, and changes in limb temperature, making this model a great fit to study neuropathic pain preclinically. pSNL is an advantageous model to study neuropathic pain as it reproduces many symptoms observed in humans with neuropathic pain. Furthermore, the surgical procedure is relatively fast and straightforward to perform. Unilateral pSNL of one limb allows for comparison between the ipsilateral and contralateral paws, as well as evaluation of central sensitization. To induce chronic neuropathic hypersensitivity, a 9-0 non-absorbable nylon thread is used to ligate the dorsal third of the sciatic nerve. This article describes the surgical procedure and characterizes the development of chronic neuropathic pain through multiple commonly used behavioral tests. As a plethora of innovative therapies are now being investigated to treat chronic pain, this article provides crucial concepts for standardization and an accurate description of surgeries required to induce neuropathic pain.
• Sivanesan, E., Shankar, H., Patwardhan, A. M., Kumar, V., Ibrahim, M., Goel, V., & Darrow, D. (2022). Procedure-Related Outcomes Including Readmission Following Spinal Cord Stimulator Implant Procedures: A Retrospective Cohort Study.. Anesthesia and analgesia, 134(4), 843-852. doi:10.1213/ane.0000000000005816
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  Spinal cord stimulation (SCS) has been shown to reduce opioid consumption, reduce pain, improve quality of life compared to conventional therapy, and be more effective than spine reoperation in carefully selected patients. In this study, we evaluate readmissions after SCS implantation procedures, costs, predictors, and etiologies for readmission following implantation procedures..The study was a retrospective cohort using the National Readmissions Database from 2013 to 2017. Administrative billing codes were used to identify patients undergoing SCS implantation procedures. The primary outcome of our study was 30-day readmission following the SCS implantation procedure. Continuous outcomes were compared between groups using the Student t test or Wilcoxon rank sum test. In addition, multivariable predictors of 30-day readmission were assessed by hierarchical logistic regression analysis..A total of 3737 (26.7% open surgical SCS implants [OS-SCS]) individuals admitted to the hospital for SCS implantation were included in the final cohort analysis. The cohort consisted of predominantly female patients (58.71%) and in the 50- to 64-year age group (35.46%). Patients who underwent open surgical SCS implantation had a longer length of stay during the initial admission and a higher 30-day readmission rate (9.4% vs 7% P = .01). OS-SCS, older age, lower socioeconomic status, patients with specific comorbidities (ie, hypertension or chronic obstructive pulmonary disease [COPD]), and home discharge are associated with readmission..Readmission rates after SCS implantation are around 7.7% in the United States. Infection and postoperative complications remain the top etiologies for readmission. Open surgical SCS implantation is associated with more extended initial hospitalization and a higher rate of readmission when compared to percutaneous SCS implantation procedures.
• Goel, V., Kumar, V., Agrawal, S. N., Patwardhan, A. M., Ibrahim, M., DeSimone, D. C., Sivanesan, E., Banik, R. K., & Shankar, H. (2021). Outcomes Associated With Infection of Chronic Pain Spinal Implantable Electronic Devices: Insights From a Nationwide Inpatient Sample Study. Neuromodulation : journal of the International Neuromodulation Society, 24(1), 126-134.
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  Chronic pain spinal implantable electronic devices (CPSIEDs) include devices that provide spinal cord stimulation and intrathecal drug therapy. In this study, we sought to evaluate the trends of CPSIED infections, related complications, and outcomes following the treatment of infection.
• Goel, V., Yang, Y., Kanwar, S., Banik, R. K., Patwardhan, A. M., Ibrahim, M., Sivanesan, E., & Shankar, H. (2021). Adverse Events and Complications Associated With Intrathecal Drug Delivery Systems: Insights From the Manufacturer and User Facility Device Experience (MAUDE) Database. Neuromodulation : journal of the International Neuromodulation Society, 24(7), 1181-1189.
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  Modern intrathecal drug delivery systems (IDDS) are technologically advanced to deliver medication through various automated and patient-controlled programs. They also are associated with unique complications ranging from post-operative complications, medication-related adverse events (AE), device malfunction, to refill associated AE.
• Martin, L. F., Moutal, A., Cheng, K., Washington, S. M., Calligaro, H., Goel, V., Kranz, T., Largent-Milnes, T. M., Khanna, R., Patwardhan, A., & Ibrahim, M. M. (2021). Green Light Antinociceptive and Reversal of Thermal and Mechanical Hypersensitivity Effects Rely on Endogenous Opioid System Stimulation. The journal of pain, 22(12), 1646-1656.
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  Benefits of phototherapy were characterized in multiple diseases including depression, circadian rhythm disruptions, and neurodegeneration. Studies on migraine and fibromyalgia patients revealed that green light-emitting diodes (GLED) exposure provides a pragmatic and safe therapy to manage chronic pain. In rodents, GLED reversed hypersensitivity related to neuropathic pain. However, little is known about the underlying mechanisms of GLED efficacy. Here, we sought to understand how green light modulates the endogenous opioid system. We first characterized how exposure to GLED stimulates release of β-endorphin and proenkephalin in the central nervous system of male rats. Moreover, by individually editing each of the receptors, we found that µ- and δ-opioid receptors are required for green light's antinociceptive effect in naïve rats and a model of HIV-induced peripheral neuropathy. We investigated how GLED could increase pain thresholds, and explored its potential in reversing hypersensitivity in a model of HIV-related neuropathy. Through behavioral and gene editing approaches, we identified that green light provides antinociception via modulation of the endogenous opioid system in the spinal cord. This work identifies a previously unknown mechanism by which GLED can improve pain management. Clinical translation of these results will advance the development of an innovative therapy devoid of adverse effects. PERSPECTIVE: Development of new pain management therapies, especially for HIV patients, is crucial as long-term opioid prescription is not recommended due to adverse side effects. Green light addresses this necessity. Characterizing the underlying mechanisms of this potentially groundbreaking and safe antinociceptive therapy will advance its clinical translation.
• Martin, L., Ibrahim, M., Gomez, K., Yu, J., Cai, S., Chew, L. A., Bellampalli, S. S., Moutal, A., Largent-Milnes, T., Porreca, F., Khanna, R., Olivera, B. M., & Patwardhan, A. (2021). Conotoxin contulakin-G engages a neurotensin receptor 2 /R-type calcium channel (Cav2.3) pathway to mediate spinal antinociception. Pain.
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  Intrathecal application of contulakin-G (CGX), a conotoxin peptide and a neurotensin analogue, has been demonstrated to be safe and potentially analgesic in humans. However, the mechanism of action for CGX analgesia is unknown. We hypothesized that spinal application of CGX produces antinociception through activation of the presynaptic neurotensin receptor (NTSR)2. In this study, we assessed the mechanisms of CGX antinociception in rodent models of inflammatory and neuropathic pain. Intrathecal administration of CGX, dose dependently, inhibited thermal and mechanical hypersensitivities in rodents of both sexes. Pharmacological and clustered regularly interspaced short palindromic repeats/Cas9 editing of NTSR2 reversed CGX-induced antinociception without affecting morphine analgesia. Electrophysiological and gene editing approaches demonstrated that CGX inhibition was dependent on the R-type voltage-gated calcium channel (Cav2.3) in sensory neurons. Anatomical studies demonstrated coexpression of NTSR2 and Cav2.3 in dorsal root ganglion neurons. Finally, synaptic fractionation and slice electrophysiology recordings confirmed a predominantly presynaptic effect. Together, these data reveal a nonopioid pathway engaged by a human-tested drug to produce antinociception.
• Moutal, A., Martin, L. F., Boinon, L., Gomez, K., Ran, D., Zhou, Y., Stratton, H. J., Cai, S., Luo, S., Gonzalez, K. B., Perez-Miller, S., Patwardhan, A., Ibrahim, M. M., & Khanna, R. (2021). SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia. Pain, 162(1), 243-252.
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  Global spread of severe acute respiratory syndrome coronavirus 2 continues unabated. Binding of severe acute respiratory syndrome coronavirus 2's spike protein to host angiotensin-converting enzyme 2 triggers viral entry, but other proteins may participate, including the neuropilin-1 receptor (NRP-1). Because both spike protein and vascular endothelial growth factor-A (VEGF-A)-a pronociceptive and angiogenic factor, bind NRP-1, we tested whether spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuron firing was blocked by spike protein and NRP-1 inhibitor EG00229. Pronociceptive behaviors of VEGF-A were similarly blocked through suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A "silencing" of pain through subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.
• Patwardhan, A. M., Jain, S. V., Salloum, M., Porreca, F., Patwardhan, A. M., Mata, E. I., Martin, L. F., Killgore, W. D., Khanna, R., Jones-macfarland, F. N., Jain, S. V., Ibrahim, M. M., Gunnala, P., & Goel, V. (2021). Green Light Exposure Improves Pain and Quality of Life in Fibromyalgia Patients: A Preliminary One-Way Crossover Clinical Trial.. Pain medicine (Malden, Mass.), 22(1), 118-130. doi:10.1093/pm/pnaa329
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  Fibromyalgia is a functional pain disorder in which patients suffer from widespread pain and poor quality of life. Fibromyalgia pain and its impact on quality of life are not effectively managed with current therapeutics. Previously, in a preclinical rat study, we demonstrated that exposure to green light-emitting diodes (GLED) for 8 hours/day for 5 days resulted in antinociception and reversal of thermal and mechanical hypersensitivity associated with models of injury-related pain. Given the safety of GLED and the ease of its use, our objective is to administer GLED as a potential therapy to patients with fibromyalgia..One-way crossover clinical trial..United States..We enrolled 21 adult patients with fibromyalgia recruited from the University of Arizona chronic pain clinic who were initially exposed to white light-emitting diodes and then were crossed over to GLED for 1 to 2 hours daily for 10 weeks. Data were collected by using paper surveys..When patients were exposed to GLED, but not white light-emitting diodes, they reported a significant reduction in average pain intensity on the 10-point numeric pain scale. Secondary outcomes were assessed by using the EQ-5D-5L survey, Short-Form McGill Pain Questionnaire, and Fibromyalgia Impact Questionnaire and were also significantly improved in patients exposed to GLED. GLED therapy was not associated with any measured side effects in these patients..Although the mechanism by which GLED elicits pain reduction is currently being studied, these results supporting its efficacy and safety merit a larger clinical trial.
• Patwardhan, A. M., Killgore, W. D., Jain, S. V., Salloum, M. M., Porreca, F., Patwardhan, A. M., Martin, L. F., Killgore, W. D., Khanna, R., Jones-macfarland, F. N., Jain, S. V., Ibrahim, M. M., Goel, V., Gannala, P., & Freeman, J. (2021). Evaluation of green light exposure on headache frequency and quality of life in migraine patients: A preliminary one-way cross-over clinical trial.. Cephalalgia : an international journal of headache, 41(2), 135-147. doi:10.1177/0333102420956711
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  Pharmacological management of migraine can be ineffective for some patients. We previously demonstrated that exposure to green light resulted in antinociception and reversal of thermal and mechanical hypersensitivity in rodent pain models. Given the safety of green light emitting diodes, we evaluated green light as a potential therapy in patients with episodic or chronic migraine..We recruited (29 total) patients, of whom seven had episodic migraine and 22 had chronic migraine. We used a one-way cross-over design consisting of exposure for 1-2 hours daily to white light emitting diodes for 10 weeks, followed by a 2-week washout period followed by exposure for 1-2 hours daily to green light emitting diodes for 10 weeks. Patients were allowed to continue current therapies and to initiate new treatments as directed by their physicians. Outcomes consisted of patient-reported surveys. The primary outcome measure was the number of headache days per month. Secondary outcome measures included patient-reported changes in the intensity and frequency of the headaches over a two-week period and other quality of life measures including ability to fall and stay asleep, and ability to perform work. Changes in pain medications were obtained to assess potential reduction..When seven episodic migraine and 22 chronic migraine patients were analyzed as separate cohorts, white light emitting diodes produced no significant change in headache days in either episodic migraine or chronic migraine patients. Combining data from the episodic migraine and chronic migraine groups showed that white light emitting diodes produced a small, but statistically significant reduction in headache days from (days ± SEM) 18.2 ± 1.8 to 16.5 ± 2.01 days. Green light emitting diodes resulted in a significant decrease in headache days from 7.9 ± 1.6 to 2.4 ± 1.1 and from 22.3 ± 1.2 to 9.4 ± 1.6 in episodic migraine and chronic migraine patients, respectively. While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes. Conclusions regarding pain medications reduction with green light emitting diode exposure were not possible. No side effects of light therapy were reported. None of the patients in the study reported initiation of new therapies..Green light emitting diodes significantly reduced the number of headache days in people with episodic migraine or chronic migraine. Additionally, green light emitting diodes significantly improved multiple secondary outcome measures including quality of life and intensity and duration of the headache attacks. As no adverse events were reported, green light emitting diodes may provide a treatment option for those patients who prefer non-pharmacological therapies or may be considered in complementing other treatment strategies. Limitations of this study are the small number of patients evaluated. The positive data obtained support implementation of larger clinical trials to determine possible effects of green light emitting diode therapy.This study is registered with clinicaltrials.gov under NCT03677206.
• Patwardhan, A. M., Sivanesan, E., Shannon, C., Shankar, H., Patwardhan, A. M., Moran, B., Kaizer, A. M., Ibrahim, M. M., Goel, V., & Deweerth, J. C. (2021). Opioid Prescriptions by Pain Medicine Physicians in the Medicare Part D Program: A Cross-Sectional Study.. Anesthesia and analgesia, 132(6), 1748-1755. doi:10.1213/ane.0000000000005399
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  Pain medicine physicians (PMP) are a group of physicians with background training in various primary specialties with interest and expertise in managing chronic pain disorders. Our objective is to analyze prescription drug (PD) claims from the Medicare Part D program associated with PMP to gain insights into patterns, associated costs, and potential cost savings areas..The primary data source for Part D claims data is the Centers for Medicare and Medicaid Services (CMS) Chronic Conditions Data Warehouse, which contains Medicare Part D prescription drug events (PDE) records received through the claims submission cutoff date. Only providers with taxonomies of pain management (PM) and interventional pain management (IPM) were included in the study. The analysis of PDE was restricted to drugs with >250 claims. The distribution of claims and costs were analyzed based on drug class and provider specialty. Subsequently, we explored claims and expenses for opioid drug prescriptions in detail. Prescribing characteristics of the top 5% of providers by costs and claims were examined to gain additional insights. The costs and claims were explored for the top 10 drugs prescribed by PMP in 2017..There were a total of unique 3280 PMP-prescribed drugs with an associated expense of 652 million dollars in the 2017 Medicare Part D program. Prescriptions related to PMP account for a tiny fraction of the program's drug expenditure (0.4%). Opioids, anticonvulsants, and gabapentinoids were associated with the largest number of claims and the largest expenses within this fraction. Among opioid drug prescriptions, brand-named drugs account for a small fraction of claims (8%) compared to generic drugs. However, the expenses associated with brand name drugs were higher than generic drugs. Prescribers in the top 5% by PD costs had a higher number of claims, prescribed a higher proportion of branded medications, and had prescriptions associated with longer day supply compared to an average PMP. There were several opioid medications in the top 10 PD list by cost associated with PMP..Opioids were the most common medications among Medicare part D claims prescribed by PMP. Only 12% of the total opioid PD claims were by PMP. The top 5% of PMP prescribers had 10 times more claims than the average PMP.
• Patwardhan, A. M., Yang, Y., Sivanesan, E., Shannon, C., Shankar, H., Patwardhan, A. M., Ibrahim, M. M., Goel, V., & Banik, R. K. (2021). Industry Payments to Pain Medicine Physicians: An Analysis of the Centers for Medicare and Medicaid Services Open Payments Program.. Pain medicine (Malden, Mass.), 22(6), 1376-1386. doi:10.1093/pm/pnaa450
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  To analyze industry payments to pain medicine physicians in the United States..Retrospective cohort study using publicly available databases..The study includes U.S. pain medicine physicians (PMPs) with reports in the Open Payments program from 2013 to 2018..The Centers for Medicare and Medicaid Services Open Payments program was analyzed for general, investment, and ownership payments to PMPs reported from 2013 to 2018. The nature, type, and geographic variation of payments were analyzed..The main findings of the study are as follows: 1) Payments made to PMPs constituted a small proportion of the payments made to all physicians in the United States, and the number of transactions and the total dollar amount seem to have decreased from 2016 to 2018. 2) The median number of payments among physicians with reported payments was around 4 (interquartile range: 18), and the majority of them were under $20. 3) The majority of payments were for in-kind items and services (85%) and were made for food and beverages (91%), travel and lodging (5.5%). 4) Some of the ownership and investment interest payments exceeded $500,000. 5) The top five drugs associated with physician payments included medications with opioids. 6) A very small minority of payments were made for entertainment or gifts. 7) A third of PMPs with reports had payments reported under more than one taxonomy..Overall payments made to PMPs seem to be decreasing since 2016. The majority of the payments are made for the food, beverage, and travel categories. Public and physician awareness of the Open Payments system reports is essential to promote transparency and to minimize adverse effects of financial relationships on patient care.
• Rukh, S., Ramesh, R., Purewal, S., Patwardhan, A. M., Jain, S. V., Ibrahim, M. M., Hsu, C., Goel, V., & Arif, M. Z. (2021). The effect of gender, opioid use/risk, duration of chronic pain and associated factors on response to medical/procedural intervention in chronic pain patients. The Journal of Pain, 22(5). doi:10.1016/j.jpain.2021.03.060
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  Although numerous studies have evaluated the correlation of various factors such as age/gender/opioid use on the presence of chronic pain, very few have evaluated whether such factors determine how well a patient will respond to a medical/procedural intervention. In this retrospective study, we evaluated various factors that affected response to intervention and whether the type of intervention (medical vs procedural) affected the degree of response. In a study approved by the University of Arizona IRB, Electronic Medical Records (EMRs) were obtained from the Banner University of Arizona pain clinic. From the 2,980 EMRs of adult patients a total of 371 EMRs with different chronic pain conditions were randomly selected and appropriate variables were extrapolated from the charts. Response to medical/procedural intervention was measured by patient reported outcomes for pain and quality of life measures. Data were analyzed by linear regression. The sampled population had 2:3 male/female ratio was and mean age of 54.5 years. We found that the higher initial pain score, and higher opioid risk score, were negatively associated with response to the intervention. Regardless of initial pain score, females and patients with more than one pain sites were likely to respond to the intervention. Interestingly, duration of pain or amount of the opioids had no effect on the degree of response patients had after the intervention. Finally, patients were likely to respond favorably to a procedural intervention compared to medication alone. Our study points towards numerous factors that may affect response to an intervention offered in a chronic pain clinic and procedural intervention is likely going to result in greater reduction in pain compared to medication alone. Future studies will need to evaluate whether the response varies by the type of pain and type of procedure. National Institute of Health (NIH K08 NS104272).
• Slepian, M. J., Patwardhan, A. M., Slepian, M. J., Patwardhan, A. M., Martin, L. F., Ibrahim, M. M., & Cheng, K. (2021). Mechanisms and Pathways of Pain Photobiomodulation: A Narrative Review.. The journal of pain, 22(7), 763-777. doi:10.1016/j.jpain.2021.02.005
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  A growing body of evidence supports the modulation of pain by light exposure. As such, phototherapy is being increasingly utilized for the management of a variety of pain conditions. The modes of delivery, and hence applications of phototherapy, vary by wavelength, intensity, and route of exposure. As such, differing mechanisms of action exist depending upon those parameters. Cutaneous application of red light (660 nm) has been shown to reduce pain in neuropathies and complex regional pain syndrome-I, whereas visual application of the same wavelength of red light has been reported to exacerbate migraine headache in patients and lead to the development of functional pain in animal models. Interestingly visual exposure to green light can result in reduction in pain in variety of pain conditions such as migraine and fibromyalgia. Cutaneous application typically requires exposure on the order of minutes, whereas visual application requires exposure on the order of hours. Both routes of exposure elicit changes centrally in the brainstem and spinal cord, and peripherally in the dorsal root ganglia and nociceptors. The mechanisms of photobiomodulation of pain presented in this review provide a foundation in furtherance of exploration of the utility of phototherapy as a tool in the management of pain. PERSPECTIVE: This review synopsizes the pathways and mechanisms through which light modulates pain and the therapeutic utility of different colors and exposure modalities of light on pain. Recent advances in photobiomodulation provide a foundation for understanding this novel treatment for pain on which future translational and clinical studies can build upon.
• Washington, S. M., Patwardhan, A., Moutal, A., Martin, L. F., Largent-milnes, T. M., Kranz, T., Khanna, R., Ibrahim, M. M., Goel, V., Cheng, K., & Calligaro, H. (2021). Green Light Antinociceptive and Reversal of Thermal and Mechanical Hypersensitivity Effects Rely on Endogenous Opioid System Stimulation.. The journal of pain. doi:10.1016/j.jpain.2021.05.006
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  Benefits of phototherapy were characterized in multiple diseases including depression, circadian rhythm disruptions, and neurodegeneration. Studies on migraine and fibromyalgia patients revealed that green light-emitting diodes (GLED) exposure provides a pragmatic and safe therapy to manage chronic pain. In rodents, GLED reversed hypersensitivity related to neuropathic pain. However, little is known about the underlying mechanisms of GLED efficacy. Here, we sought to understand how green light modulates the endogenous opioid system. We first characterized how exposure to GLED stimulates release of β-endorphin and proenkephalin in the central nervous system of male rats. Moreover, by individually editing each of the receptors, we found that µ- and δ-opioid receptors are required for green light's antinociceptive effect in naïve rats and a model of HIV-induced peripheral neuropathy. We investigated how GLED could increase pain thresholds, and explored its potential in reversing hypersensitivity in a model of HIV-related neuropathy. Through behavioral and gene editing approaches, we identified that green light provides antinociception via modulation of the endogenous opioid system in the spinal cord. This work identifies a previously unknown mechanism by which GLED can improve pain management. Clinical translation of these results will advance the development of an innovative therapy devoid of adverse effects. PERSPECTIVE: Development of new pain management therapies, especially for HIV patients, is crucial as long-term opioid prescription is not recommended due to adverse side effects. Green light addresses this necessity. Characterizing the underlying mechanisms of this potentially groundbreaking and safe antinociceptive therapy will advance its clinical translation.
• Ibrahim, M. M. (2020). Evaluation of green light exposure on headache frequency and quality of life in migraine patients: A preliminary one-way cross-over clinical trial. Cephalalgia.
• Ibrahim, M. M. (2020). SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia. Pain.
• Martin, L., Porreca, F., Mata, E. I., Salloum, M., Goel, V., Gunnala, P., Killgore, W. D., Jain, S., Jones-MacFarland, F. N., Khanna, R., Patwardhan, A., & Ibrahim, M. M. (2020). Green Light Exposure Improves Pain and Quality of Life in Fibromyalgia Patients: A Preliminary One-Way Crossover Clinical Trial. Pain medicine (Malden, Mass.).
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  Fibromyalgia is a functional pain disorder in which patients suffer from widespread pain and poor quality of life. Fibromyalgia pain and its impact on quality of life are not effectively managed with current therapeutics. Previously, in a preclinical rat study, we demonstrated that exposure to green light-emitting diodes (GLED) for 8 hours/day for 5 days resulted in antinociception and reversal of thermal and mechanical hypersensitivity associated with models of injury-related pain. Given the safety of GLED and the ease of its use, our objective is to administer GLED as a potential therapy to patients with fibromyalgia.
• Patwardhan, A. M., Yang, Y., Sivanesan, E., Shankar, H., Patwardhan, A. M., Kanwar, S., Ibrahim, M. M., Goel, V., & Banik, R. K. (2020). Adverse Events and Complications Associated With Intrathecal Drug Delivery Systems: Insights From the Manufacturer and User Facility Device Experience (MAUDE) Database.. Neuromodulation : journal of the International Neuromodulation Society. doi:10.1111/ner.13325
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  Modern intrathecal drug delivery systems (IDDS) are technologically advanced to deliver medication through various automated and patient-controlled programs. They also are associated with unique complications ranging from post-operative complications, medication-related adverse events (AE), device malfunction, to refill associated AE..To systematically analyze real-world complications and AE reported on the Food and Drug Administration's Manufacturer and User Facility Device Experience database (MAUDE) associated with IDDS among patients predominantly with chronic pain disorders..MAUDE database was sampled for a month four times a year during the study period, February 2018 to February 2019. The database was resampled every six months till August 2020 to evaluate for any additional reported cases during the index months. The two FDA approved IDDS, were included. AE were broadly classified into causes related to catheter malfunction, pump malfunction, biologic, and medication-related AE..A total of 1001 reports were included in the final analysis. The top three reasons for adverse report are infection/erosion (15.7%, n = 157), motor stall (12.4%, n = 125) and adverse medication reactions (11.8%, n = 119), respectively. There were five deaths among patients with IDDS. Epidural hematoma (n = 3) after IDDS surgery resulted in a death and residual neurological deficits after surgical evacuation. Programming errors, medication concentration discrepancy, and failure to turn on the pump after reprogramming are various preventable causes of medication-related IDDS AEs..Analysis of AE associated with IDDS from the MAUDE database provided a real-world perspective different from reported registry complications. Awareness and vigilance of preventable IDDS-related complications is the first step toward mitigating risks to provide safe and effective intrathecal drug delivery for chronic pain management.
• Goel, V., Patwardhan, A. M., Ibrahim, M., Howe, C. L., Schultz, D. M., & Shankar, H. (2019). Complications associated with stellate ganglion nerve block: a systematic review. Regional anesthesia and pain medicine.
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  Stellate ganglion nerve blockade (SGNB) is a vital tool in our armamentarium for the treatment of various chronic pain syndromes. SGNB can be performed using the traditional landmark-based approach, or with image guidance using either fluoroscopy or ultrasound. In this review, we systematically analyzed reported SGNB-related complications between 1990 and 2018. Seven databases were queried for SGNB between January 1, 1990 and November 27, 2018. Search results of the complications associated with SGNB were reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Out of a total of 1909 articles, 67 articles met our inclusion criteria, yielding 260 cases with adverse events. In 134 of the 260 (51.5%) cases, SGNB was performed with image guidance. Sixty-four (24.6%) and 70 (26.9%) of the complication cases reported the use of ultrasound and fluoroscopy guidance, respectively. One hundred and seventy-eight (68.4%) patients had medication-related or systemic side effects, and 82 (31.5%) had procedure-related or local side effects. There was one report of death due to massive hematoma leading to airway obstruction. There was one case report of quadriplegia secondary to pyogenic cervical epidural abscess and discitis following an SGNB. Complications following SGNB have been reported with both landmark-based techniques and with imaging guidance using fluoroscopy or ultrasound. In our systematic review, most adverse events that were reported occurred during or shortly after SGNB. Vigilance, American Society of Anesthesiologists standard monitors for conscious sedation, and accessibility to resuscitation equipment are vital to the safe performance of SGNB.
• Goel, V., Patwardhan, A. M., Ibrahim, M., Shankar, H., & Schultz, D. M. (2019). Indented intrathecal drug delivery system with loss of reservoir volume. Regional anesthesia and pain medicine.
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  We report two patients who underwent elective revision surgery were found to have reduced reservoir volumes and indented bottom shield of intrathecal drug delivery system (IDDS).
• Ibrahim, M. M. (2019). Complications associated with stellate ganglion nerve block: a systematic review. Regional Anesthesia & Pain Medicine.
• Khanna, R., Patwardhan, A., Yang, X., Li, W., Cai, S., Ji, Y., Chew, L. A., Dorame, A., Bellampalli, S. S., Schmoll, R. W., Gordon, J., Moutal, A., Vanderah, T. W., Porreca, F., & Ibrahim, M. M. (2019). Development and Characterization of An Injury-free Model of Functional Pain in Rats by Exposure to Red Light. The journal of pain : official journal of the American Pain Society, 20(11), 1293-1306.
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  We report the development and characterization of a novel, injury-free rat model in which nociceptive sensitization after red light is observed in multiple body areas reminiscent of widespread pain in functional pain syndromes. Rats were exposed to red light-emitting diodes (RLED) (LEDs, 660 nm) at an intensity of 50 Lux for 8 hours daily for 5 days resulting in time- and dose-dependent thermal hyperalgesia and mechanical allodynia in both male and female rats. Females showed an earlier onset of mechanical allodynia than males. The pronociceptive effects of RLED were mediated through the visual system. RLED-induced thermal hyperalgesia and mechanical allodynia were reversed with medications commonly used for widespread pain, including gabapentin, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs. Acetaminophen failed to reverse the RLED induced hypersensitivity. The hyperalgesic effects of RLED were blocked when bicuculline, a gamma-aminobutyric acid-A receptor antagonist, was administered into the rostral ventromedial medulla, suggesting a role for increased descending facilitation in the pain pathway. Key experiments were subjected to a replication study with randomization, investigator blinding, inclusion of all data, and high levels of statistical rigor. RLED-induced thermal hyperalgesia and mechanical allodynia without injury offers a novel injury-free rodent model useful for the study of functional pain syndromes with widespread pain. RLED exposure also emphasizes the different biological effects of different colors of light exposure. PERSPECTIVE: This study demonstrates the effect of light exposure on nociceptive thresholds. These biological effects of red LED add evidence to the emerging understanding of the biological effects of light of different colors in animals and humans. Understanding the underlying biology of red light-induced widespread pain may offer insights into functional pain states.
• Khanna, R., Patwardhan, A., Yang, X., Li, W., Cai, S., Ji, Y., Chew, L. A., Dorame, A., Bellampalli, S. S., Schmoll, R. W., Gordon, J., Moutal, A., Vanderah, T. W., Porreca, F., & Ibrahim, M. M. (2019). Erratum to ‛Development and Characterization of An Injury-free Model of Functional Pain in Rats by Exposure to Red Light': The Journal of Pain 20 (2019) 1293-1306. The journal of pain : official journal of the American Pain Society, 20(12), 1509.
• Garami, A., Ibrahim, M., Gilbraith, K., Khanna, R., Pakai, E., Miko, A., Pinter, E., Romanovsky, A. A., Porreca, F., & Patwardhan, A. M. (2018). In Reply. Anesthesiology, 129(2), 378-379.
• Patwardhan, A., Matika, R., Gordon, J., Singer, B., Salloum, M., & Ibrahim, M. (2018). Exploring the Role of Chronic Pain Clinics: Potential for Opioid Reduction. Pain physician, 21(6), E603-E610.
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  The management of chronic nonmalignant pain with high-dose opioids has partially contributed to the current opioid epidemic, with some responsibility shared by chronic pain clinics. Traditionally, both primary care providers and patients used chronic pain clinics as a source for continued medical management of patients on high-dose opioids, often resulting in tolerance and escalating doses. Although opioids continue to be an important component of the management of some chronic pain conditions, improvement in function and comfort must be documented. Pain clinics are ideally suited for reducing opioid usage while improving pain and function with the use of a multimodal approach to pain management. We assessed whether the application of multimodal treatment directed by pain specialists in a pain clinic provides for improved function and reduced dosages of opioid analgesics.
• Zhang, H., Lund, D. M., Ciccone, H. A., Staatz, W. D., Ibrahim, M. M., Largent-Milnes, T. M., Seltzman, H. H., Spigelman, I., & Vanderah, T. W. (2018). Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain.
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  Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain. Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients' quality of life. By contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP. Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP. Our studies using a syngeneic murine model of CIBP show that both acute and sustained administration of a peripherally restricted CB1R agonist, 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI), significantly alleviated spontaneous pain behaviors in the animals. This analgesic effect by PrNMI can be reversed by a systemic administration but not spinal injection of SR141716, a selective CB1R antagonist. In addition, the cancer-induced bone loss in the animals was not exacerbated by a repeated administration of PrNMI. Furthermore, catalepsy and hypothermia, the common side effects induced by cannabinoids, were measured at the supratherapeutic doses of PrNMI tested. PrNMI induced mild sedation, yet no anxiety or a decrease in limb movements was detected. Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects. Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.
• Garami, A., Ibrahim, M., Gilbraith, K., Khanna, R., Pakai, E., Miko, A., Pinter, E., Romanovsky, A. A., Porreca, F., & Patwardhan, A. M. (2017). Transient Receptor Potential Vanilloid 1 Antagonists Prevent Anesthesia-induced Hypothermia and Decrease Postincisional Opioid Dose Requirements in Rodents. Anesthesiology, 127(5), 813-823.
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  Intraoperative hypothermia and postoperative pain control are two important clinical challenges in anesthesiology. Transient receptor potential vanilloid 1 has been implicated both in thermoregulation and pain. Transient receptor potential vanilloid 1 antagonists were not advanced as analgesics in humans in part due to a side effect of hyperthermia. This study tested the hypothesis that a single, preincision injection of a transient receptor potential vanilloid 1 antagonist could prevent anesthesia-induced hypothermia and decrease the opioid requirement for postsurgical hypersensitivity.
• Grenald, S. A., Young, M. A., Wang, Y., Ossipov, M. H., Ibrahim, M. M., Largent-Milnes, T. M., & Vanderah, T. W. (2017). Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology, 116, 59-70.
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  The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2 agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability. We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, in rodent models of acute and chronic inflammatory, post-operative, and neuropathic pain using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Co-administration of morphine with JWH015 synergistically inhibited preclinical inflammatory, post-operative and neuropathic-pain in a dose- and time-dependent manner; no synergy was observed for nociceptive pain. Opioid-induced side effects of impaired gastrointestinal transit and CPP were significantly reduced in the presence of JWH015. Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.
• Ibrahim, M. M. (2017). Long-Lasting Antinociception Effects of Green light in Acute and Chronic Pain in Rats. Pain.
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  AbstractTreatments for chronic pain are inadequate, and new options are needed. Nonpharmaceutical approaches are especially attractive with many potential advantages including safety. Light therapy has been suggested to be beneficial in certain medical conditions such as depression, but this approach remains to be explored for modulation of pain. We investigated the effects of light-emitting diodes (LEDs), in the visible spectrum, on acute sensory thresholds in naive rats as well as in experimental neuropathic pain. Rats receiving green LED light (wavelength 525 nm, 8 h/d) showed significantly increased paw withdrawal latency to a noxious thermal stimulus; this antinociceptive effect persisted for 4 days after termination of last exposure without development of tolerance. No apparent side effects were noted and motor performance was not impaired. Despite LED exposure, opaque contact lenses prevented antinociception. Rats fitted with green contact lenses exposed to room light exhibited antinociception arguing for a role of the visual system. Antinociception was not due to stress/anxiety but likely due to increased enkephalins expression in the spinal cord. Naloxone reversed the antinociception, suggesting involvement of central opioid circuits. Rostral ventromedial medulla inactivation prevented expression of light-induced antinociception suggesting engagement of descending inhibition. Green LED exposure also reversed thermal and mechanical hyperalgesia in rats with spinal nerve ligation. Pharmacological and proteomic profiling of dorsal root ganglion neurons from green LED-exposed rats identified changes in calcium channel activity, including a decrease in the N-type (CaV2.2) channel, a primary analgesic target. Thus, green LED therapy may represent a novel, nonpharmacological approach for managing pain.
• Ibrahim, M. M. (2017). Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. Pain.
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  Pain. 2017 Feb;158(2):347-360. doi: 10.1097/j.pain.0000000000000767.Long-lasting antinociceptive effects of green light in acute and chronic pain in rats.Ibrahim MM1, Patwardhan A, Gilbraith KB, Moutal A, Yang X, Chew LA, Largent-Milnes T, Malan TP, Vanderah TW, Porreca F, Khanna R.Author informationAbstractTreatments for chronic pain are inadequate, and new options are needed. Nonpharmaceutical approaches are especially attractive with many potential advantages including safety. Light therapy has been suggested to be beneficial in certain medical conditions such as depression, but this approach remains to be explored for modulation of pain. We investigated the effects of light-emitting diodes (LEDs), in the visible spectrum, on acute sensory thresholds in naive rats as well as in experimental neuropathic pain. Rats receiving green LED light (wavelength 525 nm, 8 h/d) showed significantly increased paw withdrawal latency to a noxious thermal stimulus; this antinociceptive effect persisted for 4 days after termination of last exposure without development of tolerance. No apparent side effects were noted and motor performance was not impaired. Despite LED exposure, opaque contact lenses prevented antinociception. Rats fitted with green contact lenses exposed to room light exhibited antinociception arguing for a role of the visual system. Antinociception was not due to stress/anxiety but likely due to increased enkephalins expression in the spinal cord. Naloxone reversed the antinociception, suggesting involvement of central opioid circuits. Rostral ventromedial medulla inactivation prevented expression of light-induced antinociception suggesting engagement of descending inhibition. Green LED exposure also reversed thermal and mechanical hyperalgesia in rats with spinal nerve ligation. Pharmacological and proteomic profiling of dorsal root ganglion neurons from green LED-exposed rats identified changes in calcium channel activity, including a decrease in the N-type (CaV2.2) channel, a primary analgesic target. Thus, green LED therapy may represent a novel, nonpharmacological approach for managing pain.
• Ibrahim, M. M., Patwardhan, A., Gilbraith, K. B., Moutal, A., Yang, X., Chew, L. A., Largent-Milnes, T., Malan, T. P., Vanderah, T. W., Porreca, F., & Khanna, R. (2017). Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. Pain, 158(2), 347-360.
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  Treatments for chronic pain are inadequate, and new options are needed. Nonpharmaceutical approaches are especially attractive with many potential advantages including safety. Light therapy has been suggested to be beneficial in certain medical conditions such as depression, but this approach remains to be explored for modulation of pain. We investigated the effects of light-emitting diodes (LEDs), in the visible spectrum, on acute sensory thresholds in naive rats as well as in experimental neuropathic pain. Rats receiving green LED light (wavelength 525 nm, 8 h/d) showed significantly increased paw withdrawal latency to a noxious thermal stimulus; this antinociceptive effect persisted for 4 days after termination of last exposure without development of tolerance. No apparent side effects were noted and motor performance was not impaired. Despite LED exposure, opaque contact lenses prevented antinociception. Rats fitted with green contact lenses exposed to room light exhibited antinociception arguing for a role of the visual system. Antinociception was not due to stress/anxiety but likely due to increased enkephalins expression in the spinal cord. Naloxone reversed the antinociception, suggesting involvement of central opioid circuits. Rostral ventromedial medulla inactivation prevented expression of light-induced antinociception suggesting engagement of descending inhibition. Green LED exposure also reversed thermal and mechanical hyperalgesia in rats with spinal nerve ligation. Pharmacological and proteomic profiling of dorsal root ganglion neurons from green LED-exposed rats identified changes in calcium channel activity, including a decrease in the N-type (CaV2.2) channel, a primary analgesic target. Thus, green LED therapy may represent a novel, nonpharmacological approach for managing pain.
• Moutal, A., Yang, X., Li, W., Gilbraith, K. B., Luo, S., Cai, S., François-Moutal, L., Chew, L. A., Yeon, S. K., Bellampalli, S. S., Qu, C., Xie, J. Y., Ibrahim, M. M., Khanna, M., Park, K. D., Porreca, F., & Khanna, R. (2017). CRISPR/Cas9 editing of Nf1 gene identifies CRMP2 as a therapeutic target in neurofibromatosis type 1-related pain that is reversed by (S)-Lacosamide. Pain, 158(12), 2301-2319.
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  Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain. Targeted intrathecal delivery of guide RNA/Cas9 nuclease plasmid in combination with a cationic polymer was used to generate allele-specific C-terminal truncation of neurofibromin, the protein encoded by the Nf1 gene. Rats with truncation of neurofibromin, showed increases in voltage-gated calcium (specifically N-type or CaV2.2) and voltage-gated sodium (particularly tetrodotoxin-sensitive) currents in dorsal root ganglion neurons. These gains-of-function resulted in increased nociceptor excitability and behavioral hyperalgesia. The cytosolic regulatory protein collapsin response mediator protein 2 (CRMP2) regulates activity of these channels, and also binds to the targeted C-terminus of neurofibromin in a tripartite complex, suggesting a possible mechanism underlying NF1 pain. Prevention of CRMP2 phosphorylation with (S)-lacosamide resulted in normalization of channel current densities, excitability, as well as of hyperalgesia following CRISPR/Cas9 truncation of neurofibromin. These studies reveal the protein partners that drive NF1 pain and suggest that CRMP2 is a key target for therapeutic intervention.
• Patwardhan, A. M., Matika, R. W., Patwardhan, A. M., Matika, R. W., & Ibrahim, M. M. (2017). The importance of body temperature: An anesthesiologist's perspective.. Temperature (Austin, Tex.), 4(1), 9-12. doi:10.1080/23328940.2016.1243509
• Patwardhan, A. M., Sirianni, J., Patwardhan, A. M., & Ibrahim, M. M. (2015). Chronic pain syndromes, mechanisms, and current treatments.. Progress in molecular biology and translational science, 131, 565-611. doi:10.1016/bs.pmbts.2015.01.004
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  Although acute pain is a physiological response warning the human body of possible harm, chronic pain can be a pathological state associated with various diseases or a disease in itself. In the United States alone, around one-third of the population has experienced a chronic pain condition and annual cost to the society is in the range of 500-600 billion dollars.(1) It should be noted that if at all this is a very modest estimate, it surpasses the costs associated with cancer, heart disease, and diabetes combined.(1) Unfortunately, despite these humongous costs, the treatment of chronic pain is inadequate.(1) Chronic pain affects individuals in a variety of forms, and below we highlight some of the most common chronic pain conditions seen in a pain clinic. Most of these disorders are difficult to treat and typically require multimodal therapy including pharmacotherapy, behavioral modification, and targeted interventions. We have summarized the scope of each disorder, clinical features, proposed mechanisms, and current therapies for them (Table 1).
• Ibrahim, M. M. (2011). Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids.. Anesthesiology.
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  BACKGROUND:Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain. This study tests the hypothesis that regular aerobic exercise leads to sustained reversal of neuropathic pain by activating endogenous opioid-mediated pain modulatory systems.METHODS:After baseline measurements, the L5 and L6 spinal nerves of male Sprague-Dawley rats were tightly ligated. Animals were randomized to sedentary or 5-week treadmill exercise-trained groups. Thermal and tactile sensitivities were assessed 23 h after exercise, using paw withdrawal thresholds to von Frey filaments and withdrawal latencies to noxious heat. Opioid receptor antagonists were administered by subcutaneous, intrathecal, or intracerebroventricular injection. Opioid peptides were quantified using immunohistochemistry with densitometry.RESULTS:Exercise training ameliorated thermal and tactile hypersensitivity in spinal nerve-ligated animals within 3 weeks. Sensory hypersensitivity returned 5 days after discontinuation of exercise training. The effects of exercise were reversed by using systemically or intracerebroventricularly administered opioid receptor antagonists and prevented by continuous infusion of naltrexone. Exercise increased β-endorphin and met-enkephalin content in the rostral ventromedial medulla and the mid-brain periaqueductal gray area.CONCLUSIONS:Regular moderate aerobic exercise reversed signs of neuropathic pain and increased endogenous opioid content in brainstem regions important in pain modulation. Exercise effects were reversed by opioid receptor antagonists. These results suggest that exercise-induced reversal of neuropathic pain results from an up-regulation of endogenous opioids.
• Ibrahim, M. M. (2009). Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain. Eur J Neuroscience.
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  The clinically important opioid fentanyl, administered acutely, enhances mechanical hypersensitivity in a model of surgical pain induced by plantar incision. Activity of neurokinin-1 (NK-1) receptor-expressing ascending spinal neurons, descending pathways originating in the rostral ventromedial medulla (RVM), and spinal dynorphin are necessary for the development and maintenance of hyperalgesia during sustained morphine exposure, suggesting that these mechanisms may also be important in opioid enhancement of surgical pain. Therefore, we examined the roles of these mechanisms in sensory hypersensitivity produced by acute fentanyl administration in rats not undergoing surgical incision and in rats undergoing plantar incision. In non-operated rats, fentanyl induced analgesia followed by immediate and long-lasting sensory hypersensitivity, as previously described. Fentanyl also enhanced pain sensitivity induced by plantar incision. Ablation of NK-1-expressing spinal neurons by pre-treatment with substance P-Saporin reduced sensory hypersensitivity in fentanyl-treated rats and, to a lesser extent, in fentanyl-treated rats with a surgical incision. Microinjection of lidocaine into the RVM completely reversed fentanyl-induced sensory hypersensitivity and fentanyl enhancement of incision-induced sensory hypersensitivity. RVM lidocaine injection resulted in a slight reduction of incision-induced sensory hypersensitivity in the absence of fentanyl pre-treatment. Spinal dynorphin content increased by 30 +/- 7% and 66 +/- 17% in fentanyl- and fentanyl/incision-treated rats. Spinal administration of antiserum to dynorphin attenuated sensory hypersensitivity in fentanyl-treated rats. These data support a partial role of NK-1 receptor-containing ascending pathways and a crucial role of descending facilitatory pathways in fentanyl-induced hyperalgesia and in the enhanced hyperalgesia produced by fentanyl treatment following surgical incision.
• Ibrahim, M. M. (2008). Constitutive activity at the cannabinoid CB1 receptor is required for behavioral response to noxious chemical stimulation of TRPV1: antinociceptive actions of CB1 inverse agonists. J Neuroscience.
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  The potential modulation of TRPV1 nociceptive activity by the CB(1) receptor was investigated here using CB(1) wild-type (WT) and knock-out (KO) mice as well as selective CB(1) inverse agonists. No significant differences were detected in baseline thermal thresholds of ICR, CB(1)WT or CB(1)KO mice. Intraplantar capsaicin produced dose- and time-related paw flinch responses in ICR and CB(1)WT mice and induced plasma extravasation yet minimal responses were seen in CB(1)KO animals with no apparent differences in TRPV1 channel expression. Capsaicin-evoked CGRP release from spinal cord tissue and capsaicin-evoked action potentials on isolated skin-nerve preparation were significantly decreased in CB(1)KO mice. Pretreatment with intraplantar galanin and bradykinin, compounds known to sensitize TRPV1 receptors, restored capsaicin-induced flinching in CB(1)KO mice. The possibility that constitutive activity at the CB(1) receptor is required to maintain the TRPV1 receptor in a "sensitized" state was tested using CB(1) inverse agonists. The CB(1) inverse agonists elicited concentration-related inhibition of capsaicin-induced calcium influx in F-11 cells and produced dose-related inhibition of capsaicin-induced flinching in ICR mice. These data suggest that constitutive activity at the CB(1) receptor maintains the TRPV1 channel in a sensitized state responsive to noxious chemical stimuli. Treatment with CB(1) inverse agonists may promote desensitization of the channel resulting in antinociceptive actions against chemical stimulus modalities. These studies propose possible therapeutic exploitation of a novel mechanism providing pain relief by CB(1) inverse agonists.
• Ibrahim, M. M. (2008). Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neuroscience.
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  The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the mu receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.
• Ibrahim, M. M. (2007). Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. J Med Chem.
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  The identification of the CB2 cannabinoid receptor has provided a novel target for the development of therapeutically useful cannabinergic molecules. We have synthesized benzo[ c]chromen-6-one analogs possessing high affinity and selectivity for this receptor. These novel compounds are structurally related to cannabinol (6,6,9-trimethyl-3-pentyl-6 H-benzo[ c]chromen-1-ol), a natural constituent of cannabis with modest CB2 selectivity. Key pharmacophoric features of the new selective agonists include a 3-(1',1'-dimethylheptyl) side chain and a 6-oxo group on the cannabinoid tricyclic structure that characterizes this class of compounds as "cannabilactones." Our results suggest that the six-membered lactone pharmacophore is critical for CB2 receptor selectivity. Optimal receptor subtype selectivity of 490-fold and subnanomolar affinity for the CB2 receptor is exhibited by a 9-hydroxyl analog 5 (AM1714), while the 9-methoxy analog 4b (AM1710) had a 54-fold CB2 selectivity. X-ray crystallography and molecular modeling show the cannabilactones to have a planar ring conformation. In vitro testing revealed that the novel compounds are CB2 agonists, while in vivo testing of cannabilactones 4b and 5 found them to possess potent peripheral analgesic activity.
• Lai, J., Zhang, W., Vanderah, T. W., Stucky, C. L., Porreca, F., Ossipov, M. H., Medler, K., Malan, T., Luo, M. C., Lai, J., Ibrahim, M. M., Fioravanti, B., & Defelice, M. (2007). (641): Modulation of TRPV1 channels by the CB1 cannabinoid receptor. The Journal of Pain, 8(4), S11. doi:10.1016/j.jpain.2007.02.052
• Ibrahim, M. M. (2006). CB2 cannabinoid receptor mediation of antinociception. Pain.
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  Management of acute pain remains a significant clinical problem. In preclinical studies, CB2 cannabinoid receptor-selective agonists inhibit nociception without producing central nervous system side effects. The CB2 receptor-selective agonist AM1241 produces antinociceptive effects that are antagonized by CB2, but not CB1, receptor-selective antagonists, suggesting that activation of CB2 receptors results in antinociception. However, it has not been possible to definitively demonstrate that these effects are mediated by CB2 receptors, because we have lacked the pharmacological tools to confirm the in vivo receptor selectivity of the antagonists used. Further, recent evidence for cannabinoid-like receptors beyond CB1 and CB2 raises the possibility that AM1241 exerts its antinociceptive effects at uncharacterized CB2-like receptors that are also inhibited by AM630. The experiments reported here further test the hypothesis that CB2 receptor activation inhibits nociception. They evaluated the antinociceptive actions of AM1241 and the less-selective CB2 receptor agonist WIN55,212-2 in wild-type (CB2+/+) mice and in mice with genetic disruption of the CB2 receptor (CB2-/- mice). AM1241 inhibited thermal nociception in CB2+/+ mice, but had no effect in CB2-/- littermates. WIN55,212-2 produced equivalent antinociception in CB1+/+ and CB1-/- mice, while its antinociceptive effects were reduced in CB2-/- compared to CB2+/+ mice. The effects of morphine were not altered in CB2-/- compared to CB2+/+ mice. These data strongly suggest that AM1241 produces antinociception in vivo by activating CB2 cannabinoid receptors. Further, they confirm the potential therapeutic relevance of CB2 cannabinoid receptors for the treatment of acute pain.
• Ibrahim, M. M. (2005). CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A..
• Ibrahim, M. M. (2004). Mouse strains that lack spinal dynorphin upregulation after peripheral nerve injury do not develop neuropathic pain. Neuroscience.
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  Several experimental models of peripheral neuropathy show that a significant upregulation of spinal dynorphin A and its precursor peptide, prodynorphin, is a common consequence of nerve injury. A genetically modified mouse strain lacking prodynorphin does not exhibit sustained neuropathic pain after nerve injury, supporting a pronociceptive role of elevated levels of spinal dynorphin. A null mutation of the gamma isoform of protein kinase C (PKCgamma KO [knockout]), as well as an inbred mouse strain, 129S6, also does not manifest behavioral signs of neuropathic pain following peripheral nerve injury. The objective of this study was to extend our observations to these genetic models to test the hypothesis that elevated levels of spinal dynorphin are essential for the maintenance of abnormal pain. In PKCgamma wild-type mice and the outbred mouse strain ICR, ligation of the L5 and L6 spinal nerves (SNL) elicited both tactile hypersensitivity and thermal hyperalgesia. Both strains showed a significant elevation in dynorphin in the lumbar spinal dorsal horn following SNL. Spinal administration of an anti-dynorphin A antiserum blocked the thermal and tactile hypersensitivity in both strains of mice. However, the PKCgamma KO mice and the 129S6 mice (which express PKCgamma) did not show abnormal pain after SNL; neither strain showed elevated levels of spinal dynorphin. The multiple phenotypic deficits in PKCgamma KO mice confound the interpretation of the proposed role of PKCgamma-expressing spinal neurons in neuropathic pain states. Additionally, the data show that the regulation of spinal dynorphin expression is a common critical feature of expression of neuropathic pain.
• Ibrahim, M. M. (2004). Production of paradoxical sensory hypersensitivity by alpha 2-adrenoreceptor agonists. Anesthesiology.
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  BACKGROUND:Administration of opioid receptor agonists is followed by paradoxical sensory hypersensitivity. This hypersensitivity has been suggested to contribute to the antinociceptive tolerance observed with opioids. The authors hypothesized that alpha 2-adrenoreceptor agonists, which also produce antinociceptive tolerance, would produce sensory hypersensitivity.METHODS:alpha 2-Adrenoreceptor agonists were administered to male Sprague-Dawley rats as a single subcutaneous injection, a continuous subcutaneous infusion, a single intrathecal injection, or a continuous intrathecal infusion. Thermal sensitivity was determined using latency to withdrawal of the hind paw from radiant heat. Tactile sensitivity was determined using withdrawal threshold to von Frey filaments. Spinal dynorphin content was measured by enzyme immunoassay.RESULTS:Single systemic or intrathecal injections of clonidine or dexmedetomidine produced antinociception followed by delayed thermal and tactile hypersensitivity. Six-day systemic or intrathecal infusion of clonidine produced tactile and thermal hypersensitivity observed even during clonidine infusion. Sensory hypersensitivity was prevented by coadministration of the alpha 2-adrenoreceptor-selective antagonist idazoxan or the N-methyl-D-aspartate receptor-selective antagonist MK-801. Six-day infusion of intrathecal clonidine increased dynorphin content in dorsal lumbar spinal cord. MK-801 and dynorphin antiserum reversed clonidine-induced sensory hypersensitivity.CONCLUSIONS:alpha 2-Adrenoreceptor agonists produce sensory hypersensitivity that may be analogous to that produced by opioids. Sensory hypersensitivity was prevented by idazoxan, demonstrating that it is mediated by alpha 2 receptors. Clonidine infusion increased spinal dynorphin content. Sensory hypersensitivity was prevented or reversed by MK-801 and dynorphin antiserum, implicating N-methyl-D-aspartate receptors and spinal dynorphin in its production. Clinicians should be mindful of the possibility of drug-induced hyperalgesia in patients treated with alpha 2-adrenoreceptor agonists.
• Ibrahim, M. M. (2003). Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A..
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  We designed AM1241, a selective CB2 cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB1 receptors (CB1-/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.
• Ibrahim, M. M. (2003). CB2 cannabinoid receptor agonists: pain relief without psychoactive effects?. Curr Opin Pharmacology.
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  Cannabinoid receptor agonists significantly diminish pain responses in animal models; however, they exhibit only modest analgesic effects in humans. The relative lack of efficacy in man may be because of the dose limitations imposed by psychoactive side effects. Cannabinoid agonists that selectively target CB(2) (peripheral) cannabinoid receptors should be free of psychoactive effects, perhaps allowing for more effective dosing. CB(2) receptor activation inhibits acute, inflammatory and neuropathic pain responses in animal models. In preclinical studies, CB(2) receptor agonists do not produce central nervous system effects. Therefore, they show promise for the treatment of acute and chronic pain without psychoactive effects.
• Ibrahim, M. M. (2003). Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology.
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  BACKGROUND:Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia.METHODS:Rats were injected in the hind paw with carrageenan or capsaicin. Paw withdrawal latencies were measured using a focused thermal stimulus. The effects of peripheral CB2 receptor activation were determined by using local injection of AM1241. CB2 receptor mediation of the actions of AM1241 was shown by using the CB2 receptor-selective antagonist AM630 and the CB1 receptor-selective antagonist AM251.RESULTS:AM1241 fully reversed carrageenan-induced inflammatory thermal hyperalgesia when injected into the inflamed paw. In contrast, AM1241 injected into the contralateral paw had no effect, showing that its effects were local. AM1241 also reversed the local edema produced by hind paw carrageenan injection. The effects of AM1241 were reversed by the CB2 receptor-selective antagonist AM630, but not by the CB1 receptor-selective antagonist AM251. AM1241 also inhibited flinching and thermal hyperalgesia produced by hind paw capsaicin injection.CONCLUSIONS:Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.
• Ibrahim, M. M. (2002). Inhibition of pain responses by activation of CB(2) cannabinoid receptors.. Chem Phys Lipids.
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  Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence demonstrates that CB(1) cannabinoid receptor activation inhibits pain responses. Recently, the synthesis of CB(2) cannabinoid receptor-selective agonists has allowed testing whether CB(2) receptor activation inhibits pain. CB(2) receptor activation is sufficient to inhibit acute nociception, inflammatory hyperalgesia, and the allodynia and hyperalgesia produced in a neuropathic pain model. Studies using site-specific administration of agonist and antagonist have suggested that CB(2) receptor agonists inhibit pain responses by acting at peripheral sites. CB(2) receptor activation also inhibits edema and plasma extravasation produced by inflammation. CB(2) receptor-selective agonists do not produce central nervous system (CNS) effects typical of cannabinoids retaining agonist activity at the CB(1) receptor. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise for the treatment of pain and inflammation without CNS side effects.
• Ibrahim, M. M. (2001). Allodynia and hyperalgesia produced by specific inhibition of spinal c-fos expression: lack of correlation with dynorphin content. J Pain.
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  Inhibition of spinal Fos expression increases formalin-induced nociception and decreases spinal prodynorphin messenger ribonucleic acid (mRNA), suggesting that Fos modulates nociception by inducing dynorphin synthesis. This study tests the hypothesis that Fos modulates sensitivity to other somatic stimuli, such that inhibition of Fos expression will result in tactile allodynia and thermal hyperalgesia. In addition, it correlates the somatosensory effects of inhibition of Fos expression with spinal dynorphin content. Antisense oligodeoxynucleotide (ODN) to c-fos mRNA was administered by intrathecal infusion. Tactile sensitivity was tested by probing the hindpaw with von Frey filaments. Thermal sensitivity was quantitated by using withdrawal latency to radiant heat. Two percent formalin was injected into the dorsal hindpaw, and flinches were quantitated. Fos was quantitated by counting immunoreactive cells. Dynorphin was measured by immunoassay. Intrathecal antisense, but not mismatch, ODN resulted in tactile allodynia, thermal hyperalgesia, and hyperalgesia to formalin-induced nociception. Antisense ODN decreased Fos-like immunoreactivity after formalin injection but did not alter Jun-like immunoreactivity. Antisense ODN had differing effects on spinal dynorphin content, depending on the method of administration. These experiments show a role of Fos in modulating somatosensory sensitivity and suggest that induction of dynorphin synthesis is not the sole mechanism by which Fos does so.
• Ibrahim, M. M. (2001). Formation of lipid reserves in fat body and eggs of the yellow fever mosquito, Aedes aegypti. J Insect Physiol.
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  We examined the accumulation of lipids in adult females of the mosquito, Aedes aegypti. Females emerged with about 100 µg lipid in the fat body. With access to sugar water lipids increased over seven days to 300 µg. After a blood meal on day five, sugar-fed females accumulated 120-140 µg of lipids in their ovaries within 2 days. At the same time the lipid content of the fat body decreased by 100 µg, indicating transfer of lipids from fat body to oocytes. Experiments in which fat body lipids were prelabelled support this conclusion. Label was transferred to oocytes: in mature oocytes the specific radioactivity of lipids was 80% of the specific radioactivity of prelabeled fat body lipids. Components of blood meals are also used to synthesize oocyte lipids. Fat bodies of females starved for four days had only 27 µg of lipids left. When these females were given a blood meal, they matured oocytes, although the number of ooyctes was reduced and ovaries contained only half the amount of lipids found in ovaries of females which had first fed on sugar water. Fat body lipids of these females had only slightly increased to 36 µg. This demonstrates that female Ae. aegypti use sugar to synthesize lipids, but they can also use components of blood for this purpose.
• Malan, T. P., Vanderah, T. W., Porreca, F., Mata, H. P., Malan, T. P., Malan, P. T., Makriyannis, A., Liu, Q., Ibrahim, M. M., & Deng, H. (2001). CB2 cannabinoid receptor-mediated peripheral antinociception.. Pain, 93(3), 239-245. doi:10.1016/s0304-3959(01)00321-9
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  Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB(1) receptor in the production of antinociception. However, the capacity of CB(2) receptors, which are located outside the central nervous system (CNS), to produce antinociception is not known. Using AM1241, a CB(2) receptor-selective agonist, we demonstrate that CB(2) receptors produce antinociception to thermal stimuli. Injection of AM1241 in the hindpaw produced antinociception to a stimulus applied to the same paw. Injection of an equivalent dose of AM1241 into the paw contralateral to the side of testing did not. The antinociceptive actions of AM1241 were blocked by the CB(2) receptor-selective antagonist AM630, but not by the CB(1) receptor-selective antagonist AM251. AM1241 also produced antinociception when injected systemically (intraperitoneally). The antinociceptive actions of systemic AM1241 were blocked by injection of AM630 into the paw where the thermal stimulus was applied, but not the contralateral paw. These findings demonstrate the local, peripheral nature of CB(2) cannabinoid antinociception. AM1241 did not produce the CNS cannabinoid effects of hypothermia, catalepsy, inhibition of activity or impaired ambulation, while this tetrad of effects was produced by the mixed CB(1)/CB(2) receptor agonist WIN55,212-2. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise clinically for the treatment of pain without CNS cannabinoid side effects.
• Ibrahim, M. M. (2000). Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neuroscience.
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  The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the mu receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.
• Ibrahim, M. M. (2000). Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve-injured rats.. Pain.
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  Neuropathic pain is often associated with the appearance of pain in regions not related to the injured nerve. One mechanism that may underlie neuropathic pain is abnormal, spontaneous afferent drive which may contribute to NMDA-mediated central sensitization by the actions of glutamate and by the non-opioid actions of spinal dynorphin. In the present study, injuries to lumbar or sacral spinal nerves elicited elevation in spinal dynorphin content which correlated temporally and spatially with signs of neuropathic pain. The increase in spinal dynorphin content was coincident with the onset of tactile allodynia and thermal hyperalgesia. Injury to the lumbar (L(5)/L(6)) spinal nerves produced elevated spinal dynorphin content in the ipsilateral dorsal spinal quadrant at the L(5) and L(6) spinal segments and in the segments immediately adjacent. Lumbar nerve injury elicited ipsilateral tactile allodynia and thermal hyperalgesia of the hindpaw. In contrast, S(2) spinal nerve ligation elicited elevated dynorphin content in sacral spinal segments and bilaterally in the caudal lumbar spinal cord. The behavioral consequences of S(2) spinal nerve ligation were also bilateral, with tactile allodynia and thermal hyperalgesia seen in both hindpaws. Application of lidocaine to the site of S(2) ligation blocked thermal hyperalgesia and tactile allodynia of the hindpaws suggesting that afferent drive was critical to maintenance of the pain state. Spinal injection of antiserum to dynorphin A((1-17)) and of MK-801 both blocked thermal hyperalgesia, but not tactile allodynia, of the hindpaw after S(2) ligation. These data suggest that the elevated spinal dynorphin content consequent to peripheral nerve injury may drive sensitization of the spinal cord, in part through dynorphin acting directly or indirectly on the NMDA receptor complex. Furthermore, extrasegmental increases in spinal dynorphin content may partly underlie the development of extraterritorial neuropathic pain.
• Ibrahim, M. M. (1999). Loss of antiallodynic and antinociceptive spinal/supraspinal morphine synergy in nerve-injured rats: restoration by MK-801 or dynorphin antiserum. Brain Res.
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  The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies.
• Malan, T. P., Porreca, F., Ossipov, M. H., Malan, T. P., Ibrahim, M. M., Chawla, M., & Bian, D. (1998). PERIPHERAL NERVE INJURY CAUSES MULTISEGMENTAL ALLODYNIA AND A MULTISEGMENTAL INCREASE IN SPINAL DYNORPHIN CONTENT. Anesthesiology, 89(Supplement), 754A. doi:10.1097/00000542-199809130-00060

Poster Presentations

• Segar, J., Farr, K., Junak, M., Roe, D., Ehsani Chimeh, S., Jiralerspong, S., Ibrahim, M. M., & Vanderah, T. W. (2022, December). Evaluation of Dronabinol to Decrease Opioid Use for Cancer- Induced Bone Pain. San Antonio Breast Cancer Symposium. San Antonio Texas.
• Ibrahim, M. M. (2016, May). 8. Transient Receptor Channel Vanilloid-1 Antagonist as a Pharmacological Treatment for Preemptive Analgesia and Reducing Anesthesia-Induced. Western Anesthesia Resident’s Conference. San Francisco, CA.
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  Transient Receptor Channel Vanilloid-1 Antagonist as a Pharmacological Treatment for Preemptive Analgesia and Reducing Anesthesia-Induced Hypothermia Joshua Garza, MD1, Andras Garami, MD, PhD2, Mohab Ibrahim, MD, PhD1, Frank Porreca, PhD1, Andrej Romanovsky, MD, PhD3, Amol Patwardhan, MD, PhD1 Western Anesthesia Resident’s Conference, San Francisco, CA May 2016
• Ibrahim, M. M. (2016, November). Long lasting Antinociceptive effects of green light in acute and chronic pain in rats. Society for Neuroscience.
• Ibrahim, M. M. (2002, May). Relief of neuropathic pain by activation of peripheral CB2 cannabinoid receptors. Abstracts of the Tenth World Congress on Pain, International Association for the Study of Pain.
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  Ibrahim MM, Mata HP, Deng H, Liu Q, Vanderah TW, Porreca F, Lai J, Makriyannis A, Malan TP. Relief of neuropathic pain by activation of peripheral CB2 cannabinoid receptors. Abstracts of the Tenth World Congress on Pain, International Association for the Study of Pain. 2002; 1169.
• Ibrahim, M. M. (2001, June). CB2 cannabinoid peripheral analgesia. Journal of Pain.
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  Ibrahim M, Deng H, Mata H, Vanderah T, Porreca F, Makriyannis A, Malan TP. CB2 cannabinoid peripheral analgesia. Journal of Pain, 2001; 2: 661.
• Ibrahim, M. M. (2001, May). AM1241, a selective cannabinoid CB2 receptor agonist, relieves neuropathic pain. Society for Neuroscience Annual Meeting Abstracts.
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  Ibrahim MM, Mata HP, Deng H, Vanderah TW, Porreca F, Makriyannis A, Malan TP. 2001. AM1241, a selective cannabinoid CB2 receptor agonist, relieves neuropathic pain. Society for Neuroscience Annual Meeting Abstracts 2001; 716.16.
• Ibrahim, M. M. (1998, June). Peripheral Nerve Injury Causes Multisegmental Allodynia and a Multisegmental Increase in Spinal Dynorphin Content. Anesthesiology.
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  Malan TP, Ibrahim M, Ossipov MH, Bian D, Chawla M, Porreca F. Peripheral Nerve Injury Causes Multisegmental Allodynia and a Multisegmental Increase in Spinal Dynorphin Content. Anesthesiology 1998; 89: A753.
• Ibrahim, M. M. (1999, May). Repeated spinal opioid administration or peripheral nerve injury elicits abnormal pain in ICR, but not in PKCKO or 129SvEv mice. Society for Neuroscience Abstracts.
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  Ibrahim M, Vanderah TW, Gardell LR, Zhong CM, Malan TP, Lai J, and Porreca F. Repeated spinal opioid administration or peripheral nerve injury elicits abnormal pain in ICR, but not in PKCKO or 129SvEv mice. Society for Neuroscience Abstracts, 1999.
• Ibrahim, M. M. (1999, October). Repeated spinal opioid administration produces abnormal pain and antinociceptive tolerance which is reversed by dynorphin antiserum. Society for Neuroscience Abstracts.
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  Gardell LR, Vanderah TW, Burgess SF, Ibrahim M, Zhong CM, Ossipov MH, Lai J, Malan TP, and Porreca F. Repeated spinal opioid administration produces abnormal pain and antinociceptive tolerance which is reversed by dynorphin antiserum. Society for Neuroscience Abstracts. 1999.
• Ibrahim, M. M. (1998, June). Spatial and temporal correlation of spinal dynorphin content with behavioral signs of nerve injury. Society for Neuroscience Abstracts.
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  Ibrahim M, Chawla M, Chengmin Z, Lai J, Porreca F, Malan TP. Spatial and temporal correlation of spinal dynorphin content with behavioral signs of nerve injury. Society for Neuroscience Abstracts, 1998.

Reviews

• Ibrahim, M. M. (2018. Peripherally Restricted Cannabinoids 1 Receptor Agonist as a Novel Analgesic in Cancer-Induced Bone Pain.
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  Hong Zhang, Dominique M. Lund, Haley A. Ciccone, William D. Staatz, Mohab M. Ibrahim, Tally M. Largent-Miles, Herbert H. Seltzman, Igor Spigelman, Todd W. Vanderah. Peripherally Restricted Cannabinoids 1 Receptor Agonist as a Novel Analgesic in Cancer-Induced Bone Pain. Pain. 159(9):1814-1823, (2018 Sep.)

Others

• Ibrahim, M. M. (2019, December). Researchers Explore A Drug-Free Idea To Relieve Chronic Pain: Green Light. NPR. https://www.npr.org/sections/health-shots/2019/12/15/787138928/researchers-explore-a-drug-free-idea-to-relieve-chronic-pain-green-light
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• Ibrahim, M. M. (2019, October). In the War on Opioids 525-nm LEDs Offer Hope. The International Society for Optics and Photonics. https://www.spie.org/news/spie-professional-magazine-archive/2019-october/in-the-war-on-opioids-green-leds-offer-hope?SSO=1
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  News Article