title: 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.
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 7days post CCI. Therefore, the sex-specific p38 activation and signaling is confined to the spinal cord in inflammatory and neuropathic pain conditions.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA. Electronic address: sarah.taves@duke.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Taves
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA.
authors.forename: Temugin
authors.initials: T
authors.lastname: Berta
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA.
authors.forename: Da-Lu
authors.initials: DL
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gan
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Van de Ven
authors.affiliation: Department of Pharmacy and Biochemistry, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA. Electronic address: ru-rong.ji@duke.edu.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D000818:Animals; D003986:Dibenzocycloheptenes / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012737:Sex Factors; D013116:Spinal Cord / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D003986:Dibenzocycloheptenes; D047428:Protein Kinase Inhibitors; C572387:skepinone-L; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Inflammatory pain; MAPK; Male; Microglia; Neuropathic pain; Sex; p38