Pregabalin produces analgesia in males but not females in an animal model of chronic widespread muscle pain

Abstract

Introduction: Pregabalin, which acts on the a2d-1 subunit of voltage-gated calcium channels, relieves $50% of pain in a third of individuals with fibromyalgia. Thus far, preclinical studies of pregabalin have predominantly used male animals. Objectives: The purpose of our study was to investigate potential sex differences in the analgesic efficacy of pregabalin that may contribute to disparities in human outcomes. Methods: We used a mouse model of chronic widespread muscle pain (CWP) to test the effects of pregabalin on muscle hyperalgesia, nonreflexive pain, and motor behaviors. The CWP pain model combines 2 pH 4.0 saline injections, spaced 5 days apart, into the gastrocnemius muscle and produces bilateral muscle hyperalgesia. Furthermore, we explored sex differences in the mRNA and protein expression of the a2d-1 subunit of voltage-gated calcium channels in the dorsal horn of the spinal cord and dorsal root ganglia after development of CWP. Results: Pregabalin fully attenuated muscle hyperalgesia bilaterally in male but not female mice with equal motor deficits produced in both sexes. In addition, using the conditioned place preference test, mice of both sexes with CWP spent significantly more time in the pregabalin-paired chamber compared with baseline, but not significantly greater than pain-free controls. Chronic widespread muscle pain produced no changes in a2d-1 subunit mRNA or protein expression in the dorsal horn of the spinal cord or dorsal root ganglia in either sex. Conclusion: Overall, these findings indicate pregabalin may be more effective in treating CWP in males, but the factors leading to these differences are not fully understood.