Elucidating the Role of Testosterone in the Descending Pain Pathway after Activity-induced Pain

Abstract

We developed an activity-induced musculoskeletal pain model that produces behavioral sex differences in which females develop widespread hyperalgesia of longer duration, while males develop localized pain for shorter durations. Previously, we determined that testosterone mediates the behavioral phenotype in male and female mice, and that there are sex-dependent differences in expression of SERT in the RVM with females showing increased expression. The current study examined the role of RVM in mediating the testosterone-dependent behavioral phenotype and SERT expression. The pain model was induced by two injections (pH 5.0 saline) into the left gastrocnemius muscle combined with 6 minutes of fatiguing muscle contraction. Hyperalgesia was tested with withdrawal threshold of the gastrocnemius using force sensitive tweezers. To determine if testosterone mediates antinociception centrally, we implanted a guide cannula into the RVM and microinjected drugs to modulate sex hormone receptors in male and female mice. We also tested whether systemic changes in sex hormones modulated SERT in the RVM and whether blockade of SERT in the RVM modulates pain behavior. Blockade of either estrogen receptors (p<.01) or aromatase (p<.05) in the RVM resulted in contralateral hyperalgesia in male mice but had no effect in female mice (p=.457). In females, activation of androgen receptors with dihydrotestosterone reversed the behavioral phenotype causing unilateral hyperalgesia (p<.05). Also, systemic testosterone reduced the increased SERT expression in the RVM in female mice (p=.009); there was no change in gonadectomized males (p=.915). Microinjection of a SERT inhibitor into the RVM reversed ipsilateral hyperalgesia in both male (p<.05) and female (p<.05) mice. Our data suggests that males convert testosterone in the RVM to estrogen to protect from development of widespread hyperalgesia. Conversely, activation of androgen receptors in the RVM in female mice leads to antinociception which may be through modulation of SERT expression. Grant support from AR073187.