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

尽管最近我们对疼痛机制的理解取得了进展，但总体上几乎没有 改善慢性疼痛的临床管理。现在人们认识到，有效的慢性疼痛 管理取决于关键的生物变量，特别是患者的性别。因此，迫切需要 根据不同性别的疼痛机制定制慢性疼痛管理方案。因此，我们的 长期目标是定义控制慢性疼痛的性别依赖机制，并利用这一知识 开发针对性别的治疗方法，以更有效地管理慢性疼痛。性腺激素(GNH) 在疼痛机制的性别依赖性调节中起关键作用。在关于以下方面的知识方面存在差距 生长激素是如何调节慢性疼痛的。这项提案的目标是确定监管机制 被GNH招募用于性别依赖的慢性疼痛控制。基于现有的文献和我们的 初步数据，我们提出了一种全新的调节机制，在慢性阻塞性肺疾病 疼痛的可塑性，从急性疼痛到慢性疼痛的转变是由基因的远程控制控制的 函数通过依赖于GNH的本地翻译实现。我们的初步数据表明，催乳素受体(Prlr) 可能是这一机制的关键。在伤害感受器中，Prlr在女性中被局部翻译，但在男性中没有。 对疼痛可塑性有很大贡献的终末，仅在女性身上。例如，感官 仅在女性，神经元特异性Prlr消融可抑制IL-6诱导的超敏反应。 此外，催乳素(PRL)诱导的痛觉过敏启动，它模拟了从急性到慢性的转变 与男性相比，女性的疼痛显著增强。因此，我们的中心假设是性行为- 向慢性疼痛过渡的特定调节通过持续的局部翻译发生在 MRNAs的伤害性感受器终端，如Prlr，这基本上是由性腺控制的 荷尔蒙。拟议的研究将：1)极大地扩展我们对慢性病控制机制的认识 2)通过提供性行为的治疗靶点来提供翻译潜力- 以慢性疼痛管理为基础。我们的假设得到了相互关联但又相互独立的目标的检验。目标1 定义了伤害性终末的局部翻译、性别依赖的GNH和Prlr的贡献 痛觉过敏启动的调节。目的2考察GNH在特定性别的本地翻译中的作用。 目的3鉴定在伤害性感受器末端控制性别特异性局部翻译的Prlr序列基序。这个 拟议的研究具有创新性，因为它定义了概念上新颖的性别特异性调控机制 研究具有技术创新的小鼠基因的雌性慢性疼痛背后的神经元可塑性。这个 拟议的研究具有重要意义，因为它促进了我们对慢性疼痛的性别差异的理解 机制--一个研究不足的领域，基础科学知识的增加有可能导致 更好的治疗方法。

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.