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

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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.