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Microglial P2X4R-evoked pain hypersensitivity is sexually dimorphic in rats

Mapplebeck, Josiane C.S.a,b,c; Dalgarno, Rebeccad,e; Tu, YuShana; Moriarty, Orlaa,f; Beggs, Simona,g; Kwok, Charlie H.T.d,e; Halievski, Katherinea; Assi, Sofiaa,b; Mogil, Jeffrey S.h,i; Trang, Tuand,e; Salter, Michael W.a,b,c,*

doi: 10.1097/j.pain.0000000000001265
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Microglia–neuron signalling in the spinal cord is a key mediator of mechanical allodynia caused by peripheral nerve injury. We recently reported sex differences in microglia in pain signalling in mice: spinal mechanisms underlying nerve injury–induced allodynia are microglial dependent in male but not female mice. Whether this sex difference in pain hypersensitivity mechanisms is conserved in other species is unknown. Here, we show that in rats, the spinal mechanisms of nerve injury–induced hypersensitivity in males differ from those in females, with microglial 4 receptors">P2X4 receptors (P2X4Rs) being a key point of divergence. In rats, nerve injury produced comparable allodynia and reactive microgliosis in both sexes. However, inhibiting microglia in the spinal cord reversed allodynia in male rats but not female rats. In addition, pharmacological blockade of P2X4Rs, by an intrathecally administered antagonist, attenuated pain hypersensitivity in male rats only. Consistent with the behavioural findings, nerve injury increased cell surface expression and function of P2X4Rs in acutely isolated spinal microglia from male rats but not from female rats. Moreover, in microglia cultured from male rats, but not in those from female rats, stimulating P2X4Rs drove intracellular signalling through p38 mitogen-activated protein kinase. Furthermore, chromatin immunoprecipitation–qPCR revealed that the transcription factor IRF5 differentially binds to the P2rx4 promoter region in female rats vs male rats. Finally, mechanical allodynia was produced in otherwise naive rats by intrathecally administering P2X4R-stimulated microglia from male rats but not those from female rats. Together, our findings demonstrate the existence of sexually dimorphic pain signalling in rats, suggesting that this sex difference is evolutionarily conserved, at least across rodent species.

The spinal mechanisms underlying neuropathic pain are sexually dimorphic in rats, as microglial P2X4 receptors drive pain hypersensitivity in males but not females.The spinal mechanisms underlying neuropathic pain are sexually dimorphic in rats, as microglial 4 receptors">P2X4 receptors drive pain hypersensitivity in males but not females.

aProgram in Neuroscience & Mental Health, Hospital for Sick Children, Toronto, ON, Canada

bDepartment of Physiology, University of Toronto, Toronto, ON, Canada

cUniversity of Toronto Centre for the Study of Pain, Toronto, ON, Canada

dDepartment of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada

eDepartment of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

fInternational Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland

gUCL Great Ormond Street Institute of Child Health, London, United Kingdom

hDepartment of Psychology, McGill University, Montreal, QC, Canada

iAlan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

Corresponding author. Address: Hospital for Sick Children, 686 Bay St, Toronto, ON M5G 0A4, Canada. Tel.: (416) 813-6272; fax: (416) 813-7921. E-mail address: michael.salter@sickkids.ca (M.W. Salter).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

J.C.S. Mapplebeck and R. Dalgarno are co-first authors.

Received August 22, 2017

Received in revised form April 19, 2018

Accepted April 23, 2018

© 2018 International Association for the Study of Pain
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