Prolactin regulation of postoperative pain in males and females

 描述(由申请人提供)：尽管我们对疼痛机制的理解最近取得了进展，但在术后疼痛的临床管理方面几乎没有整体的改善。现在已经认识到，有效的术后疼痛管理取决于关键的预测因素，特别是患者的性别。临床前和临床数据表明，尽管术后疼痛水平几乎没有性别依赖性，但目前用于治疗术后疼痛的药物在止痛效果、安全性和滥用/成瘾潜力方面存在显著的性别差异。因此，迫切需要定制基于性别特异性疼痛药理学的术后疼痛管理方案。我们的长期目标是定义性别依赖的术后疼痛机制，并利用这一知识提供更有效的术后疼痛管理方案。我们最近发表的初步数据表明，手术后切口痛的临床前模型通过手术部位和脊髓中的垂体外机制导致催乳素(PRL)的性别依赖性上调。PRL受体(PRLR)在女性感觉神经元中的反应比男性更强。此外，在手术部位使用Prlr拮抗剂，尤其是在脊髓，仅在女性和所有疼痛类型中抑制术后超敏反应。这项建议的目的是明确女性PRL系统(即PRL和PRLR)对术后疼痛的特定调节的外周和脊髓机制。我们的中心假设是，垂体外PRL通过外周和脊髓机制以女性特有的方式调节术后疼痛。其基本原理是，了解促进PRL和PRLR对术后疼痛的女性特异性影响的机制将1)极大地扩展疼痛机制中的性别差异的知识；2)为开发新的治疗策略提供翻译潜力。 专为女性术后疼痛管理量身定做。我们的假设得到了相互关联但又相互独立的目标的检验。目的1评价女性和男性手术后外周终末和手术部位固有免疫细胞以及脊髓中央终末和神经胶质细胞的PRL和PrLR可塑性。目的2明确感觉神经元、先天免疫细胞和神经胶质细胞在PRL介导的术后超敏反应和持续性疼痛调节机制中的作用。目的3研究催乳素对幼稚和手术的雌雄伤害性感受器兴奋性的调节。这项拟议的研究是创新的，因为IF定义了垂体外PRL在调节术后疼痛中的性别依赖作用，以及女性术后疼痛的特定调节途径。这项拟议的研究具有重要意义，因为它促进了我们对术后疼痛机制中的性别差异的了解，并对新的基于性别的术后疼痛管理策略具有很大的翻译潜力。

 DESCRIPTION (provided by applicant): Despite recent advances in our understanding of pain mechanisms, there has been little-to-no overall improvement in the clinical management of postoperative pain. It is now recognized that effective postoperative pain management depends on key predictors, especially patient sex. Preclinical and clinical data indicate that, while postoperative pain levels show little-to-no sex-dependent dimorphisms, there are significant sex-based differences in analgesic efficacy, safety profile and abuse/addiction potential of current drugs used to treat postoperative pain. Hence, there is an urgent need to customize postoperative pain management schemes as based on sex-specific pain pharmacology. Our long-term goal is to define sex-dependent postoperative pain mechanisms, and utilize this knowledge to provide more effective postoperative pain management schemes. Our recent published and preliminary data show that a preclinical model of post-operative surgical incision pain leads to a sex-dependent up-regulation of prolactin (PRL) via extra-pituitary mechanisms at surgical sites and in the spinal cord. The PRL receptor (Prlr) is more responsive in female sensory neurons than in males. Moreover, administration of a Prlr antagonist at surgical sites, and especially in the spinal cord, suppresses postoperative hypersensitivity only in females and across all pain modalities. The objective of this proposal is to define peripheral and spinal mechanisms responsible for female-specific regulation of postoperative pain by the PRL system (i.e. PRL and Prlr). Our central hypothesis is that extra-pituitary PRL regulates postoperative pain in a female-specific manner via both peripheral and spinal mechanisms. The rationale is that understanding mechanisms contributing to the female-specific effects of PRL and Prlr on postoperative pain will 1) greatly expand knowledge of sex differences in pain mechanisms; and 2) provide translational potential for the development of novel therapeutic strategies specifically tailored for postoperative pain management in females. Our hypothesis is tested by interconnected yet independent aims. Aim 1 evaluates surgery-induced PRL and Prlr plasticity in peripheral terminals and innate immune cells at surgical sites, and central terminals and glia in spinal cord of female and males. Aim 2 defines the influences of sensory neurons, innate immune cells and glia in peripheral and spinal mechanisms of PRL- mediated regulation of postoperative hypersensitivity and ongoing pain in females and males. Aim 3 examines the regulation of nociceptor excitability by PRL in naïve and operated females and males. The proposed study is innovative since if defines the sex-dependent role of extra-pituitary PRL in regulating postoperative pain, and pathways for specific regulation of postoperative pain in females. The proposed research is significant as it advances our knowledge of sex differences in postoperative pain mechanisms, and has substantial translational potential for new sex-based postoperative pain management strategies.