Sex-specific regulation of local translation and chronic pain mechanisms in females

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Despite recent advances in our understanding of pain mechanisms, there has been little-to-no overall improvement in the clinical management of chronic pain. It is now recognized that effective chronic pain management depends on key biological variables, especially patient sex. Hence, there is an urgent need to customize chronic pain management schemes based on sex-specific pain mechanisms. Accordingly, our long-term goal is to define sex-dependent mechanisms controlling pain chronicity, and utilize this knowledge to develop sex-specific therapeutics for more effective chronic pain management. Gonadal hormones (GnH) play a key role in sex-dependent regulation of pain mechanisms. There is a gap in knowledge pertaining to how GnH regulate pain chronicity. The objective of this proposal is to identify regulatory mechanisms recruited by GnH for sex-dependent control of pain chronicity. Based on the existing literature and our preliminary data, we propose an entirely novel regulatory mechanism for sexual dimorphisms in chronic pain plasticity wherein the transition from acute to chronic pain is governed by remote control of gene function via GnH-dependent local translation. Our preliminary data suggests that the prolactin receptor (Prlr) may be a linchpin in this mechanism. Prlr is locally translated in females but not males in nociceptor terminals where it contributes strongly to pain plasticity exclusively in females. For instance, sensory neuronal specific Prlr ablation leads to a suppression of IL-6-induced hypersensitivity only in females. Moreover, Prolactin (PRL)-induced hyperalgesic priming, which models the transition from acute to chronic pain, is dramatically enhanced in females compared to males. Therefore, our central hypothesis is that sex- specific regulation of the transition to chronic pain occurs via continuous local translation in nociceptor terminals of mRNAs such as Prlr, and this is fundamentally controlled by gonadal hormones. The proposed study will: 1) greatly expand our knowledge of mechanisms controlling chronicity of pain conditions in females; and 2) provide translational potential by offering therapeutic targets for sex- based chronic pain management. Our hypothesis is tested by interconnected yet independent aims. Aim 1 defines the contribution of local translation in nociceptive terminals, GnH and Prlr in sex-dependent regulation of hyperalgesic priming. Aim 2 examines the involvement of GnH in sex-specific local translation. Aim 3 identifies Prlr sequence motifs controlling sex-specific local translation in nociceptor terminals. The proposed study is innovative because it defines the conceptually novel sex-specific regulatory mechanisms for neuronal plasticity underlying chronic pain in females with technically innovative mouse genetics. The proposed research is significant as it advances our understanding of sex differences in chronic pain mechanisms – an understudied area where increasing basic science knowledge has the potential to lead to better therapeutics.