Opioid-Induced Immune Alterations: Gender Differences

描述(申请人提供)：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，但关于个人性别如何影响阿片类药物诱导的免疫调节知之甚少。鉴于阿片类药物在临床上的广泛使用及其高滥用潜力，了解性行为与阿片类药物诱导的免疫变化的相互作用至关重要。具体目的I提供了吗啡对男性和女性接触性超敏反应(CHS)反应的药理学分析，重点是临床结果指标(即肿胀)，以及介导这些影响的免疫学和受体机制。我们的初步发现表明，吗啡对男性和女性都有促进CHS的作用，但在女性中，吗啡的效力是男性的两倍多，效果更大，而且作用持续的时间更长。这项拟议的研究将通过评估CHS部位免疫介质的作用来确定造成这种显著性别差异的特定免疫机制，包括IL-1-β、肿瘤坏死因子-α、干扰素-γ、IL-4、IL-6、IL-10和一氧化氮的表达。研究还将测试吗啡激活男性和女性不同中枢和外周阿片受体类型的假设。特定目标II将确定性腺(或性)激素是否在吗啡诱导的接触性超敏(CHS)改变中调节性别差异。鉴于有充分的证据表明性腺激素对观察到的免疫功能和阿片类药物敏感性的性别差异有贡献，在分析阿片类药物诱导的免疫调节中深刻的性别差异背后的激素机制方面，消耗这些激素是合乎逻辑和关键的第一步。这项拟议的研究测试了男性和女性性腺激素缺乏是否会影响吗啡诱导的CHS变化以及这种性分化反应的特定免疫介质。具体目标三确定临床上相关阿片类药物的性别差异的普遍性，以及性别差异的大小是否与阿片类药物的相对疗效(即刺激u阿片受体的能力)有关。我们的计划是用一系列临床上重要的阿片类药物来评估阿片类药物免疫调节中的性别差异，这些药物在疗效上是不同的。我们的假设是，除了吗啡外，阿片类药物的性别差异也会很明显，与性别相关的差异的大小将与他们刺激u阿片受体的能力成反比。鉴于几乎不知道个体的性别如何与阿片类药物的免疫调节作用相互作用，拟议的研究首次促进了我们对性别在阿片类药物诱导的免疫调节中的调节作用的理解。这些研究具有临床意义，并将影响阿片类药物用于患者护理的选择，以及加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。

DESCRIPTION (provided by applicant): 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-1-beta, TNF-alpha, IFN-gamma, 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 mu 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 mu 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.