GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, But Not Female Mice

Abstract

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 (10 mg/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 alleviate thermal hypersensitivity and allodynia, respectively, in female mice. On the other hand, MS15203 treatment decreased the duration of thermal hypersensitivity 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 (PAG) 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 PAG. Treatment with MS15203 then rescued the protein levels of GPR171 in the PAG 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.

GPR171 activation regulates morphine tolerance but not withdrawal in a test-dependent manner in mice

“…not having any analgesic properties on its own on these thermal pain tests ( McDermott et al , 2019 ). The diminished antinociceptive effects in females within this study are aligned with our recent study showing that MS15203 alleviated inflammatory and neuropathic pain in male mice, but not female mice ( Ram et al , 2021 ). It is unclear why this effect of MS15203 treatment would be different between sexes or pain tests.…”

“…Several limitations of this study require future exploration. For example, we used only one dose, 10 mg/kg, of MS15203 and dose administration timeline due to the known efficacy of this dose at increasing morphine antinociception and decreasing chronic pain ( McDermott et al , 2019 ; Ram et al , 2021 ). However, whether 10 mg/kg of MS15203 over 5 days is optimal for altering morphine tolerance or withdrawal is unknown.…”

“…Another limitation is that only thermal pain tests were used, which may result in different results than mechanical or chronic pain tests (see Ram et al , 2021 ). Lastly, as was mentioned above, pretreatment with MS15203+Morphine could be due to the lingering effects of MS15203.…”

“…However, the side effect profile of this GPR171 agonist must be carefully investigated before significant resources are invested in drug discovery efforts. In addition, studies evaluating GPR171 in females are needed given that to date only one article has used females, which found reduced effects in chronic pain compared to males ( Ram et al , 2021 ). The purpose of this study was to evaluate whether repeated treatment of morphine in combination with a GPR171 agonist leads to greater side effects, such as tolerance and withdrawal in male and female mice.…”

DNA Methylation: A Target in Neuropathic Pain

“…Sex hormones, endogenous opiate functions, and genetic factors are the main reasons for these differences (91)(92)(93). For example, in preclinical trials, male and female animals respond differently to pain under the same conditions (94); female CD-1 mice required two to three times more morphine than male mice to produce the same analgesic effect (95). Furthermore, the Delta opiate receptor (DOR) helps control pain, and pain tolerance was abolished in females with DOR knockout but not in male mice (96).…”