Androgen-mediated pain-regulatory mechanisms targeting primary sensory neurons

Abstract

Given the sex differences in pain sensitivity and the prevalence of pain disorders, there is a strong need to elucidate their molecular basis. Because sex differences arise from the interactions between genetic factors and postnatal influences mediated by sex hormones, understanding how sex steroid hormones regulate pain is of particular importance. The mechanical pain threshold is lower in females than in males, whereas no sex differences are observed in thermal, chemical or inflammatory pain, consistent with findings in humans. In gonadectomized male mice, the mechanical threshold is decreased, suggesting a correlation between androgen levels and mechanical pain sensitivity. The androgen receptor (AR) is widely expressed in regions involved in pain transmission, with prominent nuclear localization in the dorsal root ganglia of male mice. In nociceptive primary sensory neuron-specific AR-conditional knockout (AR-cKO) male mice, the mechanical pain threshold is markedly reduced compared with wild-type males, whereas other pain modalities remain unchanged. Moreover, systemic androgen administration to female mice increases nuclear AR localization and elevates the mechanical pain threshold one day after treatment, but these effects are abolished in AR-cKO females. These findings demonstrate that androgen signaling in primary sensory neurons represents a key neural substrate underlying sex differences in mechanical pain sensitivity. Additionally, sex differences observed in neuropathic pain models may also be alleviated by androgen action. Further elucidation of how androgens act on their target neuronal populations is expected to advance our understanding of sex- and individual-specific differences in pain.