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

项目总结/摘要 慢性术后疼痛影响小但重要的手术人群。该项目的目标是 临床前翻译和确定脆弱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行为改变的药理学模型。这 该项目可能会发现新的见解，那些容易发展慢性术后疼痛，以及 更深入地了解潜在的遗传和基因组机制。 尽管许多具有潜在性激素水平改变的个体经历了外科手术， 大多数临床前研究并不试图解决这种高度相关的患者群体。因为它是好的 有证据表明，性激素在疼痛的发展和维持中起着关键作用，这是惊人的。在 特别地，在性腺完整的临床前手术后疼痛模型中，基础改变的性激素的作用是 相对不为人知且未被充分研究。此外，基因组范围和组织特异性的遗传变化， 性激素的变化可能会产生之前，期间，手术后尚未阐明。精确 操纵激素水平以确定慢性手术后疼痛的原因在人类中是不可能的。到 确定改善术后恢复的目标，因此，我们将利用临床知情的性别 激素改变的啮齿动物模型以及经验证的行为终点。我们的核心假设是， 脆弱的患者人群，性激素发生改变，有助于情绪的变化， 激素改变和情绪变化使这些脆弱的个体易于发生手术后慢性 痛苦为了进行这项基础工作，我们将使用分子和整个有机体的组合， 我有重要的专业知识，包括小鼠模型的切口手术，疼痛诱发， 和疼痛抑制行为读数，以及检查与基因组相关的倍数变化， 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 主要知识差距：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测量在体内监测药理学调节， 疼痛相关的行为2)由于性激素改变而发生的具体遗传改变是什么？3)是 在手术患者人群中观察到的性激素变化与术后使用和效力有关， 手术止痛药最终，这些研究将确定性激素的改变如何影响术后。 手术疼痛恢复。成功完成建议的研究可能会提高我们对性的认识 脆弱患者人群中的激素变化，以及性激素在治疗后愈合中的作用。 手术，识别相关组学相关变化，并阐明镇痛治疗方案。

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.