Estrogen Mediates the Sexual Dimorphism of GT1b-Induced Central Pain Sensitization

Abstract

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.

Sexual Dimorphism in the Mechanism of Pain Central Sensitization

“…Meanwhile, orchiectomy-subjected male mice displayed similar levels of pain sensitivity to GT1b. This finding demonstrates that male sex hormones are not involved in GT1b-induced pain sexual dimorphism [ 76 ]. Therefore, the sexually dimorphic pain central sensitization mechanism of GT1b-induced pain is distinct from that of LPS-induced pain central sensitization.…”

“…Intrathecal administration of GT1b induced spinal cord microglia activation with morphological changes such as enlarged cell bodies, microglial proliferation, and enhanced Iba-1 immunoreactivity. In addition, GT1b stimulation upregulated inflammatory cytokines such as IL-1β, TNF-α, and NADPH oxidase 2 in the spinal cord microglia [ 75 , 76 ]. Interestingly, although GT1b stimulation-evoked microglial activation and proliferation were observed in both male and female mice, pain sensitization was apparent only in the male mice [ 76 ].…”

“…In addition, GT1b stimulation upregulated inflammatory cytokines such as IL-1β, TNF-α, and NADPH oxidase 2 in the spinal cord microglia [ 75 , 76 ]. Interestingly, although GT1b stimulation-evoked microglial activation and proliferation were observed in both male and female mice, pain sensitization was apparent only in the male mice [ 76 ]. We investigated the sexually dimorphic features of spinal cord microglia activation after GT1b administration by comparing gene-expression profiles of male and female mice.…”

“…We investigated the sexually dimorphic features of spinal cord microglia activation after GT1b administration by comparing gene-expression profiles of male and female mice. DAVID Gene Ontology analysis showed that most enriched differentially expressed genes in biological processes are associated with estrogen responses, including Tph2 , Krt19 , Abcc2 , and Agtr1b genes (data are elaborated on by Lee and colleagues [ 76 ]).…”

“…Our study found that GT1b administration induced inflammasome activation in the spinal cord in a sex-dependent manner; specifically, it induced caspase-1 expression only in male mice but not female ones. To investigate whether female sex hormones affect microglial inflammasome activation upon GT1b administration, we tested the effects of estrogen on inflammasome activation in primary glia [ 76 ]. Ultimately, estrogen did not inhibit GT1b-induced caspase-1 expression in vitro, so it is likely that estrogen may indirectly inhibit glial caspase-1 transcription in vivo.…”