Opioid-Induced Immune Alterations: Sex Differences

阿片类药物引起的免疫改变：性别差异

• 批准号: 6557184
• 负责人: DONALD T LYSLE
• 金额: $ 21.61万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6557184
• 关键词: contact dermatitis; gender difference; hormone regulation /control mechanism; immunomodulators; immunopharmacology; inflammation; interferon gamma; interleukin 1; interleukin 10; interleukin 4; interleukin 6; laboratory rat; morphine; nitric oxide synthase; opiate alkaloid; opioid receptor; polymerase chain reaction; sex hormones; tumor necrosis factor alpha

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.

描述（由申请人提供）：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，但对个体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CHS在男性和女性，但在女性中，吗啡是两倍以上的效力，有一个更大的最大效果，效果持续更长的时间。拟议的研究将通过评估CHS部位免疫介质的作用来确定导致这些巨大性别差异的特定免疫机制，包括IL-1-β、TNF-α、IFN-γ、IL-4、IL-6、IL-10和一氧化氮表达。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。鉴于有充分的证据表明，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，耗尽这些激素是一个合乎逻辑的和关键的第一步，在阿片类药物诱导的免疫调节的深刻性别差异的激素机制分析。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，刺激μ阿片受体的能力）。我们的计划是评估阿片类免疫调节的性别差异与一系列临床上重要的阿片类药物，不同的沿着一个连续的疗效。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μ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，拟议的研究是第一个推进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，将影响患者护理阿片类药物的选择，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了解。