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）：最近的研究产生了有关阿片类药物的免疫调节作用的大量信息，但是关于个人性别如何影响阿片类药物诱导的免疫调节的信息知之甚少。鉴于阿片类药物的广泛临床使用及其高滥用潜力，因此了解性别与阿片类药物诱导的免疫改变的相互作用至关重要。具体目的I提供了吗啡对男性和女性接触超敏反应（CHS）反应的影响的药理分析，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。我们的最初发现表明吗啡可以增强男性和女性的CHS，但在女性中，吗啡是有效的两倍以上，具有更大的最大作用，并且效果持续了更长的时间。拟议的研究将通过评估免疫学介质在CHS部位的作用，包括IL-1-beta，TNF-Alpha，IFN-Gamma，IFN-Gamma，IL-4，IL-6，IL-6，IL-6，IL-10和一氧化物的表达来确定这些戏剧性性别差异的特定免疫机制。研究还将测试吗啡激活男性和女性中不同的中枢和外周的阿片受体类型的假设。特定的目标II将确定性腺（或性别）激素是否介导吗啡诱导的接触超敏反应（CHS）的变化中的性别差异。鉴于有充分的证据表明性腺激素有助于免疫功能和阿片类药物敏感性观察到的性别差异，因此这些激素耗尽了这些激素代表了分析阿片类药物诱导的免疫调节中性别差异的激素机制的逻辑和关键第一步。提出的研究测试男性和女性的性腺激素是否耗竭会影响吗啡诱导的CHS改变以及这种性别分化反应的特定免疫学介质。特定的目标III决定了临床相关的阿片类药物之间性别差异的普遍性，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MU阿片受体的能力）有关。我们的计划是评估阿片类药物免疫调节中的性别差异，并通过一系列临床上重要的阿片类药物在疗效的连续体中有所不同。我们的假设是，除吗啡以外的阿片类药物外，性别差异将显而易见，并且与性别相关的差异的大小将与它们刺激MU阿片受体的能力成反比。鉴于几乎没有关于个人的性别如何与阿片类药物的免疫调节作用相互作用的知之甚少，因此提出的研究是第一个促进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。这些研究具有临床重要性，将影响阿片类药物的选择，并增强我们对阿片类药物使用和滥用的不良后果的潜在性别差异的理解。