Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord |
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| Affiliation: | 1. Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA;2. Department of Neurobiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA;3. Department of Pharmacy and Biochemistry, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany;1. Program in Neurosciences & Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada;2. Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada;3. Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada;4. Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06519, USA;1. Wolfson Centre for Age-Related Diseases, King’s College London, London SE1 1UL, UK;2. Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, NY 11797, USA;1. School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, United States;2. Department of Medical Pharmacology, University of Arizona, Tucson, AZ, 85724, United States;3. Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, United States;1. Physiology, School of Medicine, National University of Ireland Galway, University Road, Galway, Ireland;2. Pharmacology and Therapeutics, School of Medicine, National University of Ireland Galway, University Road, Galway, Ireland;3. NCBES Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland Galway, University Road, Galway, Ireland;1. Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, PR China;2. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA |
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| Abstract: | Previous studies have shown that activation of p38 mitogen-activating kinase (MAPK) in spinal microglia participates in the generation of inflammatory and neuropathic pain in various rodent models. However, these studies focused on male mice to avoid confounding effects of the estrous cycle of females. Recent studies have shown that some spinal pro-inflammatory signaling such as Toll-like receptor 4-mediated signaling contributes to pain hypersensitivity only in male mice. In this study we investigated the distinct role of spinal p38 in inflammatory and neuropathic pain using a highly selective p38 inhibitor skepinone. Intrathecal injection of skepinone prevented formalin induced inflammatory pain in male but not female mice. Furthermore, intrathecal skepinone reduced chronic constriction injury (CCI) induced neuropathic pain (mechanical allodynia) in male mice on CCI-day 7 but not CCI-day 21. This male-dependent inhibition of neuropathic pain also occurred in rats following intrathecal skepinone. Nerve injury induced spinal p38 activation (phosphorylation) in CX3CR1-GFP+ microglia on CCI-day 7, and this activation was more prominent in male mice. In contrast, CCI induced comparable microgliosis and expression of the microglial markers CX3CR1 and IBA-1 in both sexes. Notably, intraperitoneal or local perineural administration of skepinone inhibited CCI-induced mechanical allodynia in both sexes of mice. Finally, skepinone only reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina IIo neurons of spinal cord slices of males 7 days post CCI. Therefore, the sex-specific p38 activation and signaling is confined to the spinal cord in inflammatory and neuropathic pain conditions. |
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| Keywords: | Microglia p38 MAPK Neuropathic pain Inflammatory pain Male Sex |
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