Opioid-Induced Immune Alterations: Gender Differences

超出所提供的空间。最近的研究已经产生了大量关于阿片类药物免疫调节作用的信息，但对个体的性别如何影响阿片类药物诱导的免疫调节知之甚少。鉴于阿片类药物的广泛临床使用及其高滥用潜力，了解性与阿片类药物诱导的免疫改变的相互作用至关重要。具体目标I提供了吗啡对男性和女性接触性超敏反应（CHS）影响的药理学分析，重点是临床结局指标（即，肿胀），以及介导这些作用的免疫学和受体机制。我们的初步研究结果表明，吗啡增强了男性和女性的CHS，但在女性中，吗啡的效力是两倍多，具有更大的最大效果，并且效果持续时间更长。本研究将通过评估CHS部位免疫介质的作用，包括IL-1 β、TNF-α、IFN-7、IL-4、IL-6、IL-10和一氧化氮的表达，确定导致这些显著性别差异的特异性免疫机制。研究还将测试吗啡激活男性和女性不同的中枢和外周阿片受体类型的假设。具体目标II将确定是否性腺（或性）激素介导吗啡诱导的接触性超敏反应（CHS）改变的性别差异。鉴于性腺激素有助于观察到的免疫功能和阿片类药物敏感性的性别差异的充分证据，耗尽这些激素是分析阿片类药物诱导的免疫调节中深刻的性别差异的激素机制的逻辑和关键的第一步。拟议的研究测试，如果在男性和女性的性腺激素耗竭影响吗啡诱导的改变CHS和这种性分化反应的特定免疫介质。具体目标III确定了临床相关阿片类药物之间性别差异的一般性，以及性别差异的大小是否与相对疗效相关（即，能够刺激阿片样物质的#阿片样物质受体）。我们的计划是评估阿片免疫调节的性别差异，使用一系列临床上重要的阿片类药物，这些药物的疗效沿着而不同。我们的假设是，除了吗啡之外，阿片类药物的性别差异将是明显的，并且性别相关差异的大小与它们刺激/x阿片受体的能力呈负相关。鉴于对个体的性别如何与阿片类药物的免疫调节作用相互作用几乎一无所知，拟议的研究首次促进了我们对阿片类药物诱导的免疫调节中性别调节作用的理解。这些研究具有临床重要性，将影响阿片类药物用于患者护理的选择，并增强我们对阿片类药物使用和滥用不良后果的潜在性别差异的理解。性能现场=

EXCEED THE SPACE PROVIDED. Recent research has produced a wealth of information on the immunomodulatory effects of opioids, but little is known about how the sex of the individual impacts opioid-induced immunomodulation. Given the widespread clinical use of opioids and their high abuse potential, an understanding of the interaction of sex with opioid- induced immune alterations is critical. Specific Aim I provides a pharmacological analysis of the effects of morphine on the contact hypersensitivity (CHS) response in males and females, with an emphasis on clinical outcome measures (i.e., swelling), as well as the immunological and receptor mechanisms that mediate these effects. Our initial findings indicate that morphine enhances CHS in both males and females, but in females, morphine is more than twice as potent, has a greater maximal effect, and'the effects persist for a longer period of time. The proposed studies will determine the specific immune mechanisms that account for these dramatic sex differences by evaluating the role of immunologic mediators at the site of CHS, including IL- l [3,TNF-c_, IFN-7, IL-4, IL-6, IL-10, and nitric oxide expression. Studies will also test hypotheses that morphine activates different central and peripheral opioid receptor types in males and females. Specific Aim II will determine if the gonadal (or sex) hormones mediate sex differences in morphine-induced alterations of contact hypersensitivity (CHS). Given the ample evidence that gonadal hormones contribute to observed sex differences in both immune function and opioid sensitivity, depleting these hormones represents a logical and critical first step in the analysis of the hormonal mechanisms underlying the profound sex differences in opioid- induced immunomodulation. The proposed studies test if gonadal hormone depletion in males and females impacts morphine-induced alterations of CHS and the specific immunologic mediators of this sexually differentiated response. Specific Aim III determines the generality of sex differences across clinically relevant opioids, and whether the magnitude of the sex differences is related to the relative efficacy (i.e., ability to stimulate the # opioid receptor) of the opioid. Our plan is to evaluate sex differences in opioid- immunomodulation with a series of clinically important opioids that differ along a continuum of efficacy. Our hypothesis is that the sex differences will be apparent with opioids other than morphine, and that the magnitude of the sex-related differences will be inversely related to their ability to stimulate the/x opioid receptor. Given that virtually nothing is known about how the sex of the individual interacts with the immunomodulatory actions of opioids, the proposed studies are the first to advance our understanding of the regulatory role of sex in opioid- induced immunomodulation. These studies have clinical importance and will influence the selection of opioids for patient care, as well as enhance our understanding of potential sex differences in the adverse consequences of opioid use and abuse. PERFORMANCE SITE ========================================Section End===========================================