Laurent F Martin

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Scholarly Contributions

Chapters

• Martin, L. F. (2025). Phototherapy. In Migraine Pain Management(pp 495-511). Academic Press. doi:https://doi.org/10.1016/B978-0-443-24705-7.00031-4

Journals/Publications

• Kopruszinski, C. M., Lee, G., Martin, L. K., Barber, K. R., Moutal, A., Dodick, D. W., Navratilova, E., & Porreca, F. (2024). A male-specific mechanism of meningeal nociceptor sensitization promoting migraine headache. Cephalalgia : an international journal of headache, 44(9), 3331024241281493.
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  We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine.
• Martin, L. F., Almuslim, M., Ismail, K. A., Ibrahim, M. M., Moutal, A., Cheng, K., Stratton, H. J., Price, T. J., Vanderah, T. W., Olivera, B. M., Khanna, R., & Patwardhan, A. (2024). The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance. Pain.
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  As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and side effect profile of CGX have never been assessed in CIBP. Here, we evaluated CGX's antinociceptive potential in a rodent model of CIBP. We hypothesized that CGX engages the NTSR2 pathway, providing pain relief with minimal tolerance and motor side effects. Our results demonstrated that CGX intrathecal injection in mice with CIBP attenuated both spontaneous pain behaviors and evoked mechanical hypersensitivity, regardless of their sex. Furthermore, the antinociceptive effect of CGX was dependent upon expression of NTSR2 and the R-type voltage-gated calcium channel (Cav2.3); gene editing of these targets abolished CGX antinociception without affecting morphine antinociception. Examination of the side effect profile of CGX demonstrated that, unlike morphine, chronic intrathecal infusion maintained antinociception with reduced tolerance in rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain.
• Stratton, H., Lee, G., Dolatyari, M., Ghetti, A., Cotta, T., Mitchell, S., Yue, X., Ibrahim, M., Dumaire, N., Salih, L., Moutal, A., François-Moutal, L., Martin, L., Navratilova, E., & Porreca, F. (2024). Nociceptors are functionally male or female: from mouse to monkey to man. Brain : a journal of neurology, 147(12), 4280-4291.
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  The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurons from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurons from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurons from a female macaque monkey. Critically, neurons recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurons. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurons and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurons. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted.
• Martin, L. F., Ibrahim, M. M., Cheng, K., Washington, S. M., Denton, M., Goel, V., Khandekar, M., Largent-Milnes, T. M., & Patwardhan, A. (2023). Green light exposure elicits anti-inflammation, endogenous opioid release and dampens synaptic potentiation to relieve post-surgical pain. The Journal of Pain, 24, 509-529. doi:10.1016/j.jpain.2022.10.011
• 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.
• Ibrahim, M. M., Martin, L. F., Patwardhan, A., Stratton, H. J., Flowers, M. E., Washington, S. M., Cheng, K., & Korah, H. E. (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.
• Ibrahim, M. M., Patwardhan, A., Martin, L. F., Cheng, K., & Calligaro, H. (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
• Martin, L. F. (2022).

  Targeting the vascular endothelial growth factor A/neuropilin 1 axis for relief of neuropathic pain

  . Pain, 164(7), 1473-1488. doi:10.1097/j.pain.0000000000002850
• Martin, L., Ibrahim, M., Gomez, K., Yu, J., Cai, S., Chew, L., Bellampalli, S., Moutal, A., Largent-Milnes, T., Porreca, F., Khanna, R., Olivera, B., & Patwardhan, A. (2022). Conotoxin contulakin-G engages a neurotensin receptor 2/R-type calcium channel (Cav2.3) pathway to mediate spinal antinociception. Pain, 163(9). doi:10.1097/j.pain.0000000000002561
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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.
• Patwardhan, A., Martin, L. F., Ramiro, I. B., Bjørn-Yoshimoto, W. E., Imperial, J. S., Gajewiak, J., Salcedo, P. F., Watkins, M., Taylor, D., Resager, W., Ueberheide, B., Bräuner-Osborne, H., Whitby, F. G., Hill, C. P., Concepcion, G. P., Olivera, B. M., & Safavi-Hemami, H. (2022). Somatostatin venom analogs evolved by fish-hunting cone snails: From prey capture behavior to identifying drug leads. Science Advances, 8(12). doi:10.1126/sciadv.abk1410
• Cheng, K., Martin, L. F., Slepian, M. J., Patwardhan, A. M., & Ibrahim, M. M. (2021). Mechanisms and Pathways of Pain Photobiomodulation: A Narrative Review. The journal of pain, 22(7), 763-777.
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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.
• 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., Bouvet, P., Chounlamountri, N., Watrin, C., Besançon, R., Pinatel, D., Meyronet, D., Honnorat, J., Buisson, A., Salin, P. A., & Meissirel, C. (2021). VEGF counteracts amyloid-β-induced synaptic dysfunction. Cell reports, 35(6), 109121.
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  The vascular endothelial growth factor (VEGF) pathway regulates key processes in synapse function, which are disrupted in early stages of Alzheimer's disease (AD) by toxic-soluble amyloid-beta oligomers (Aβo). Here, we show that VEGF accumulates in and around Aβ plaques in postmortem brains of patients with AD and in APP/PS1 mice, an AD mouse model. We uncover specific binding domains involved in direct interaction between Aβo and VEGF and reveal that this interaction jeopardizes VEGFR2 activation in neurons. Notably, we demonstrate that VEGF gain of function rescues basal synaptic transmission, long-term potentiation (LTP), and dendritic spine alterations, and blocks long-term depression (LTD) facilitation triggered by Aβo. We further decipher underlying mechanisms and find that VEGF inhibits the caspase-3-calcineurin pathway responsible for postsynaptic glutamate receptor loss due to Aβo. These findings provide evidence for alterations of the VEGF pathway in AD models and suggest that restoring VEGF action on neurons may rescue synaptic dysfunction in AD.
• 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.
  More info

  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.
• Jain, S., Porreca, F., Martin, L., Mata, E. I., Salloum, M., Goel, V., Gunnala, P., Killgore, W. D., 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, 22(1), 118-130. doi:10.1093/pm/pnaa329
• Martin, L. F. (2020).

  SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia

  . Pain, 162(1), 243-252. doi:10.1097/j.pain.0000000000002097
• Porreca, F., Killgore, W. D., Patwardhan, A. M., Martin, L. F., Jain, S. V., Salloum, M. M., Freeman, J., Khanna, R., Gannala, P., Goel, V., Jones-MacFarland, F. N., & 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, 41(2), 135-147. doi:10.1177/0333102420956711
• Benon, A., Ya, C., Martin, L., Watrin, C., Chounlamountri, N., Jaaoini, I., Honnorat, J., Pellier-Monnin, V., & Noraz, N. (2017). The Syk kinases orchestrate cerebellar granule cell tangential migration. Neuroscience, 360, 230-239.
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  The tyrosine kinases of the Syk family are essential components of the well-characterized immunoreceptor ITAM-based signaling pathway. However, ITAM-based signaling typically does not function in isolation. Instead, it is enmeshed in the molecular network controlling cellular adhesion and chemotaxis. Consistent with the increasing number of data involving ITAM-bearing molecules in neuronal functions, we previously depicted a role for Syk kinases in the establishment of neuronal connectivity. In the developing cerebellum, we found that Syk is essentially expressed in the granule cells (GC) and more importantly, phosphorylated on tyrosine residues representative of an active form of the kinase in tangentially migrating GC. In light of these findings, experiments were performed to establish the implication of Syk in this process. We showed that Syk state of phosphorylation is spatiotemporally regulated during GC ontogeny. Moreover, the analysis of external granular layer microexplants treated with a Syk pharmacological inhibitor together with the quantification of ectopic GC in Syk; ZAP-70 mutant mice brought evidence of a requirement of Syk in GC tangential migration. Syk phosphorylation was induced by EphB2 engagement and locally turned down by a not yet identified factor that could in part explain the restricted pattern of Syk phosphorylation observed along GC migratory route. Whereas Syk kinase activity appeared not essential for ephrin/Eph-mediated axon extension, it might provide polarization signals required for proper nucleus translocation during GC migration. In conclusion, Syk kinase acts downstream of receptors controlling GC tangential migration.
• De Rossi, P., Harde, E., Dupuis, J. P., Martin, L., Chounlamountri, N., Bardin, M., Watrin, C., Benetollo, C., Pernet-Gallay, K., Luhmann, H. J., Honnorat, J., Malleret, G., Groc, L., Acker-Palmer, A., Salin, P. A., & Meissirel, C. (2016). A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior. Molecular psychiatry, 21(12), 1768-1780.
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  Vascular endothelial growth factor (VEGF) is known to be required for the action of antidepressant therapies but its impact on brain synaptic function is poorly characterized. Using a combination of electrophysiological, single-molecule imaging and conditional transgenic approaches, we identified the molecular basis of the VEGF effect on synaptic transmission and plasticity. VEGF increases the postsynaptic responses mediated by the N-methyl-D-aspartate type of glutamate receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B subunit (GluNR-2B). VEGF induces a rapid redistribution of GluNR-2B at synaptic sites by increasing the surface dynamics of these receptors within the membrane. Consistently, silencing the expression of the VEGF receptor 2 (VEGFR2) in neural cells impairs hippocampal-dependent synaptic plasticity and consolidation of emotional memory. These findings demonstrated the direct implication of VEGF signaling in neurons via VEGFR2 in proper synaptic function. They highlight the potential of VEGF as a key regulator of GluNR synaptic function and suggest a role for VEGF in new therapeutic approaches targeting GluNR in depression.
• De Rossi, P., Harde, E., Dupuis, J. P., Martin, L., Chounlamountri, N., Bardin, M., Watrin, C., Benetollo, C., Pernet-Gallay, K., Luhmann, H. J., Honnorat, J., Malleret, G., Groc, L., Acker-Palmer, A., Salin, P. A., & Meissirel, C. (2016). Co-activation of VEGF and NMDA receptors promotes synaptic targeting of AMPA receptors. Molecular psychiatry, 21(12), 1647.