RT Journal Article
SR Electronic
T1 GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, but not in Female Mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.16.440030
DO 10.1101/2021.04.16.440030
A1 Akila Ram
A1 Taylor Edwards
A1 Ashley McCarty
A1 Leela Afrose
A1 Max V. McDermott
A1 Erin N. Bobeck
YR 2021
UL http://biorxiv.org/content/early/2021/04/17/2021.04.16.440030.abstract
AB Chronic pain is a growing public health crisis that requires exigent and efficacious therapeutics. GPR171 is a promising therapeutic target that is widely expressed through the brain, including within the descending pain modulatory regions. Here, we explore the therapeutic potential of the GPR171 agonist, MS15203, in its ability to alleviate chronic pain in male and female mice using a once-daily systemic dose (10mg/kg, i.p.) of MS15203 over the course of 5 days. We found that in our models of Complete Freund’s Adjuvant (CFA)-induced inflammatory pain and chemotherapy-induced peripheral neuropathy (CIPN), MS15203 did not reduce thermal hypersensitivity and allodynia, respectively, in female mice. On the other hand, MS15203 treatment decreased the duration of thermal hyper-sensitivity in CFA-treated male mice following 3 days of once-daily administration. MS15203 treatment also produced an improvement in allodynia in male mice, but not female mice, in neuropathic pain after 5 days of treatment. Gene expression of GPR171 and that of its endogenous ligand BigLEN, encoded by the gene PCSK1N, were unaltered within the periaqueductal gray in both male and female mice following inflammatory and neuropathic pain. However, following neuropathic pain in male mice, the protein levels of GPR171 were decreased in the periaqueductal gray. Treatment with MS15203 then rescued the protein levels of GPR171 in the periaqueductal gray of these mice. Taken together, our results identify GPR171 as a GPCR that displays sexual dimorphism in alleviation of chronic pain. Further, our results suggest that GPR171 and MS15203 have demonstrable therapeutic potential in the treatment of chronic pain.Competing Interest StatementThe authors have declared no competing interest.