Testosterone protects against the development of widespread muscle pain in mice.

Chronic widespread pain conditions are more prevalent in women than men, suggesting a role for gonadal hormones in the observed differences. Previously, we showed that female mice, compared to male, develop widespread, more severe, and longer-duration hyperalgesia in a model of activity-induced muscle pain. We hypothesized testosterone protects males from developing the female pain phenotype. We tested whether orchiectomy of males before induction of an activity-induced pain model produced a female phenotype and whether testosterone administration produced a male phenotype in females. Orchiectomy produced longer-lasting, more widespread hyperalgesia, similar to females. Administration of testosterone to females or orchiectomized males produced unilateral, shorter-lasting hyperalgesia. Prior studies show that the serotonin transporter (SERT) is increased in the nucleus raphe magnus (NRM) in models of chronic pain, and that blockade of SERT in the NRM reduces hyperalgesia. We examined potential sex differences in the distribution of SERT across brain sites involved in nociceptive processing using immunohistochemistry. A sex difference in SERT was found in the NRM in the activity-induced pain model; females had greater SERT immunoreactivity than males. This suggests that testosterone protects against development of widespread, long-lasting muscle pain and that alterations in SERT may underlie the sex differences.