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，但术后疼痛的临床管理几乎没有整体改善。现在人们认识到，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，虽然术后疼痛水平几乎没有性别依赖性二态性，但目前用于治疗术后疼痛的药物在镇痛疗效、安全性和滥用/成瘾潜力方面存在显著的性别差异。因此，有一个迫切需要定制术后疼痛管理计划的基础上性别特异性疼痛药理学。我们的长期目标是确定性别依赖性术后疼痛机制，并利用这些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，手术后手术切口疼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比男性更敏感。此外，在手术部位，特别是在脊髓中给予Prlr拮抗剂，仅在女性和所有疼痛模式中抑制术后超敏反应。本提案的目的是定义负责PRL系统（即PRL和Prlr）对女性术后疼痛进行特定调节的外周和脊柱机制。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性别差异的知识; 2）为开发新的治疗策略提供翻译潜力，特别是 专为女性术后疼痛管理而设计。我们的假设是由相互关联但独立的目标来检验的。目的1评价手术诱导的雌性和雄性动物外周终末和手术部位先天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介导的调节女性和男性术后超敏反应和持续疼痛的外周和脊髓机制中的影响。目的3探讨PRL对初治和手术雌、雄大鼠伤害感受器兴奋性的调节作用。这项拟议的研究是创新的，因为它定义了垂体外PRL在调节术后疼痛中的性别依赖性作用，以及女性术后疼痛的特异性调节途径。这项研究意义重大，因为它提高了我们对术后疼痛机制性别差异的认识，并对新的基于性别的术后疼痛管理策略具有巨大的转化潜力。

 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.