We have previously reported that the intrathecal (i.t.) administration of GT1b, a ganglioside, induces spinal cord microglia activation and central pain sensitization as an endogenous agonist of Toll-like receptor 2 on microglia. In this study, we investigated the sexual dimorphism of GT1b-induced central pain sensitization and the underlying mechanisms. GT1b administration induced central pain sensitization only in male but not in female mice. Spinal tissue transcriptomic comparison between male and female mice after GT1b injection suggested the putative involvement of estrogen (E2)-mediated signaling in the sexual dimorphism of GT1b-induced pain sensitization. Upon ovariectomy-reducing systemic E2, female mice became susceptible to GT1b-induced central pain sensitization, which was completely reversed by systemic E2 supplementation. Meanwhile, orchiectomy of male mice did not affect pain sensitization. As an underlying mechanism, we present evidence that E2 inhibits GT1b-induced inflammasome activation and subsequent IL-1β production. Our findings demonstrate that E2 is responsible for sexual dimorphism in GT1b-induced central pain sensitization.

It has long been recognized that men and women have different degrees of susceptibility to chronic pain. Greater recognition of the sexual dimorphism in chronic pain has resulted in increasing numbers of both clinical and preclinical studies that have identified factors and mechanisms underlying sex differences in pain sensitization. Here, we review sexually dimorphic pain phenotypes in various research animal models and factors involved in the sex difference in pain phenotypes. We further discuss putative mechanisms for the sexual dimorphism in pain sensitization, which involves sex hormones, spinal cord microglia, and peripheral immune cells. Elucidating the sexually dimorphic mechanism of pain sensitization may provide important clinical implications and aid the development of sex-specific therapeutic strategies to treat chronic pain.