Examination of sex hormone alteration on post-operative pain development and treatment

项目摘要/摘要 慢性术后疼痛影响一小部分但意义重大的手术人群。这个项目的目标是 临床前翻译和确定易感患者性激素水平改变的总体贡献 人口。这些研究将产生新的临床前性激素改变的药理学模型。这 该项目可能会对那些易患慢性术后疼痛的人以及 更好地理解潜在的遗传和基因组机制。 尽管许多性激素水平潜在改变的人都会接受外科手术， 大多数临床前研究并不试图解决这一高度相关的患者群体。因为它是好的 研究表明，性激素在疼痛的形成和维持中起着关键作用，这一点令人震惊。在……里面 特别是，基础性激素改变在性腺完整的临床前手术后疼痛模型中的作用是 相对不为人所知，研究不足。此外，全基因组和特定组织的基因变化 手术前、术中、术后性激素的变化尚不清楚。精确 通过控制激素水平来确定手术后慢性疼痛的原因在人类是不可能的。至 确定改善手术后恢复的目标，因此我们将利用临床知情的性行为 荷尔蒙改变了啮齿动物模型以及有效的行为终点。我们的中心假设是，在 易受感染的患者群体中，性激素发生改变，导致情绪改变，而且男女都有 荷尔蒙变化和情绪变化使这些脆弱的个体更容易患上手术后的慢性疾病 疼痛。为了进行这项基础性工作，我们将使用分子和整个生物体的组合 我拥有大量专业知识的方法，包括切开手术的小鼠模型，疼痛诱发的 以及疼痛抑郁行为读数，以及与基因组相关的折叠变化的检查 和特定的组织。这种能力的融合使我的独立实验室能够回答 关键知识差距：1)性激素在慢性疼痛的发展和维持中至关重要，但 是否可以通过药代动力学措施在体内监测药理调节以确定相关 疼痛相关行为？2)性激素改变会导致哪些特定的基因改变？3) 手术患者人群中的性激素变化与后激素的使用和效力相关 外科止痛药？最终，这些研究将确定性激素变化可能如何影响产后 手术疼痛恢复。成功完成建议的研究或可加强我们对性的认识 脆弱患者群体中的激素变化以及性激素在术后愈合中的作用 手术，确定与组学相关的变化，并阐明止痛治疗方案。

PROJECT SUMMARY/ABSTRACT Chronic postoperative pain affects a small but significant surgery population. The goal of this project is to preclinically translate and determine the overall contribution of altered sex hormone levels in vulnerable patient populations. These studies will generate novel preclinical sex hormone-altered pharmacological models. This project may identify new insights into those susceptible to developing chronic postoperative pain as well as a greater understanding into underlying genetic and genomic mechanisms. Although many individuals with underlying altered sex hormone levels undergo surgical procedures, most preclinical studies do not attempt to address this highly relevant patient population. As it is well documented that sex hormones play pivotal roles in pain development and maintenance, this is striking. In particular, the role of basally altered sex hormones in gonad-intact preclinical post-surgical pain models is relatively unknown and understudied. Furthermore, the genome-wide and tissue-specific genetic changes that sex hormone alterations may produce before, during, and after surgery have yet to be elucidated. Precise manipulation of hormone levels to establish chronic post-surgical pain causation is not possible in humans. To identify targets for improved post-surgical recovery we will therefore take advantage of a clinically informed sex hormone altered rodent models as well as validated behavioral endpoints. Our central hypothesis is that within vulnerable patient populations, sex hormone alterations occur, contribute to changes in mood, and both sex hormone alterations and mood changes predispose those vulnerable individuals towards post-surgical chronic pain. To pursue this fundamental work, we will use a combination of molecular and whole organism approaches in which I have significant expertise including mouse models of incisional surgery, pain-evoked and pain-depressed behavioral readouts, as well as examination of fold-changes related to both the genome and specific tissues. This convergence of capabilities uniquely positions my independent laboratory to answer key knowledge gaps: 1) Sex hormones are critical in the development and maintenance of chronic pain, but can pharmacological modulation be monitored in vivo via pharmacokinetic measures to identify correlative pain-related behaviors? 2) What specific genetic alterations occur due to sex hormone alterations? 3) Are the sex hormone alterations seen within the surgical patient population relevant to the use and potency of post- surgical analgesics? Ultimately, these studies will establish how sex hormone alterations may influence post- surgical pain recovery. Successful completion of the proposed studies may enhance our understanding of sex hormone alterations within vulnerable patient populations, and the role of sex hormones on healing after surgery, identify associated -omics related changes, and clarify analgesic treatment options.