title: Sex differences in pain: a tale of two immune cells.
abstract: Substantial evidence has implicated microglia in neuropathic pain. After peripheral nerve injury, microglia in the spinal cord proliferate and increase cell-surface expression of the purinergic receptor P2X4. Activation of P2X4 receptors results in release of brain-derived neurotrophic factor, which acts on neurons to produce disinhibition of dorsal horn neurons which transmit nociceptive information to the brain. Disinhibition of these neurons produces pain hypersensitivity, a hallmark symptom of neuropathic pain. However, elucidating this microglia-neuronal signalling pathway was based on studies using only male rodents. Recent evidence has shown that the role of microglia in pain is sexually dimorphic. Despite similar microglia proliferation in the dorsal horn in both sexes, females do not upregulate P2X4Rs and use a microglia-independent pathway to mediate pain hypersensitivity. Instead, adaptive immune cells, possibly T cells, may mediate pain hypersensitivity in female mice. This profound sex difference highlights the importance of including subjects of both sexes in preclinical pain research.
authors.affiliation: Program in Neuroscience & Mental Health, Hospital for Sick Children, Toronto, ON, Canada Department of Physiology, University of Toronto, Toronto, ON, Canada University of Toronto Centre for the Study of Pain, Toronto, ON, Canada.
authors.forename: Josiane C S
authors.initials: JCS
authors.lastname: Mapplebeck
authors.forename: Simon
authors.initials: S
authors.lastname: Beggs
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010146:Pain / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D051197:Toll-Like Receptor 4