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Voluntary wheel running reveals sex-specific nociceptive factors in murine experimental autoimmune encephalomyelitis

Mifflin, Katherine A.a; Yousuf, Muhammad S.a; Thorburn, Kevin C.b; Huang, Jennifer.b; Pérez-Muñoz, Maria Elisac; Tenorio, Gustavod; Walter, Jense,c; Ballanyi, Klausa,f; Drohomyrecky, Paulina C.g; Dunn, Shannon E.g,h,i; Kerr, Bradley J.a,b,d,*

doi: 10.1097/j.pain.0000000000001465
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Multiple sclerosis (MS) is an inflammatory, neurodegenerative autoimmune disease associated with sensory and motor dysfunction. Although estimates vary, ∼50% of patients with MS experience pain during their disease. The mechanisms underlying the development of pain are not fully understood, and no effective treatment for MS-related pain is available. Previous work from our laboratory demonstrated that voluntary exercise (wheel running) can reduce nociceptive behaviours at the disease onset in female mice with experimental autoimmune encephalomyelitis (EAE), an animal model used to study the immunopathogenesis of MS. However, given the established sex differences in the underlying mechanisms of chronic pain and MS, we wanted to investigate whether wheel running would also be effective at preventing nociceptive behaviours in male mice with EAE. C57BL/6 mice of both sexes were given access to running wheels for 1 hour/day until the disease onset, when nociceptive behaviour was assessed using von Frey hairs. Daily running effectively reduced nociceptive behaviour in female mice, but not in male mice. We explored the potential biological mechanisms for these effects and found that the reduction in nociceptive behaviour in female mice was associated with reduced levels of inflammatory cytokines from myelin-reactive T cells as well as reduced dorsal root ganglia excitability as seen by decreased calcium responses. These changes were not seen in male mice. Instead, running increased the levels of inflammatory cytokines and potentiated Ca2+ responses in dorsal root ganglia cells. Our results show that voluntary wheel running has sex-dependent effects on nociceptive behaviour and inflammatory responses in male and female mice with EAE.

Voluntary wheel running decreases nociceptive hypersensitivity associated with experimental autoimmune encephalomyelitis in a sex-specific manner and is associated with sex-specific effects on peripheral cytokine production.

aNeuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada

Departments of bPharmacology

cAgricultural, Food, and Nutritional Science

dAnesthesiology and Pain Medicine

eBiological Sciences, and

fPhysiology, University of Alberta, Edmonton, AB, Canada

gDepartment of Immunology, University of Toronto, Toronto, ON, Canada

hToronto General Research Institute, Toronto ON, Canada

iWomen's College Research Institute, Toronto, ON, Canada

Corresponding author. Address: Department of Anesthesiology and Pain Medicine, University of Alberta, Clinical Sciences Building, 2-150, Edmonton, AB T6G 2G3, Canada. Tel.:1-780-492-3380. E-mail address: bradley.kerr@ualberta.ca (B.J. Kerr).

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

K.A. Mifflin and M.S. Yousuf contributed equally to this manuscript.

Received August 30, 2018

Received in revised form October 07, 2018

Accepted October 24, 2018

© 2019 International Association for the Study of Pain
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