Immune Function and Sex Differences in Morphine Analgesia and Reward

吗啡镇痛和奖励的免疫功能和性别差异

• 批准号: 8002716
• 负责人: Jaclyn Marie Schwarz
• 金额: $ 5.05万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2013-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8002716
• 关键词: Absence of pain sensation; Affect; Brain; Dependence; Drug abuse; Effectiveness; Female; Human; Immune system; Individual; Inflammatory; Inflammatory Response; Lead; Literature; Medicine; Microglia; Morphine; Opioid; Pain; Pattern recognition receptor; Pharmaceutical Preparations; Play; Property; Rewards; Rodent; Role; Sex Characteristics; addiction; cytokine; effective therapy; experience; immune activation; immune function; insight; male; public health relevance; sex; toll-like receptor 4

DESCRIPTION (provided by applicant): Opioid drugs, such as morphine, are widely prescribed for the treatment of moderate to severe pain. While morphine and other opioids are the most effective treatment of pain, they do not provide adequate pain relief for all. For others, treatment of pain with opioids can lead down a path of dependence and addiction. An individual's sex is one major factor in determining the effectiveness of opioids for the reduction of pain and the potential for abuse liability. In both the human and the rodent literature, it has been demonstrated that males experience greater analgesia than females after opioid administration. In contrast, the rewarding properties of morphine are much greater in females than in males. Searching for a common mechanism for such disparate effects of sex on morphine-induced analgesia and reward has been difficult. However, recent evidence indicates that a critical component of morphine effectiveness involves the direct activation of microglia in the brain via the innate immune system's pattern recognition receptor, toll-like receptor (TLR) 4. This morphine-induced activation of microglia in the brain initiates the release of pro-inflammatory cytokines that markedly increase opioid-induced reward, tolerance and dependence and simultaneously decrease opioid analgesia. We therefore hypothesize that morphine-induced activation of microglia is significantly greater in females compared to males, and this glial activation may be an underlying mechanism for the differential effects of sex on morphine-induced analgesia and reward. The major objectives of this proposal are three-fold; 1) to understand basic sex differences in immune activation upon morphine treatment; 2) to understand the potential role of morphine-induced glial activation in sex differences in morphine-induced analgesia and abuse liability; and 3) to establish the specific role of microglia and begin to determine potential mechanisms. PUBLIC HEALTH RELEVANCE: The sex of an individual is a major factor in determining the effectiveness of opioid analgesia. The results of this proposal will lend insight into the role that the immune system plays in the effectiveness of morphine, as well as the potential for drug abuse between the sexes. Understanding how drugs affect males and females differently is a first step in the quest for personalized medicine.

描述（由申请人提供）：阿片类药物，例如吗啡，广泛用于治疗中度至重度疼痛。虽然吗啡和其他阿片类药物是最有效的疼痛治疗方法，但它们并不能为所有人提供足够的疼痛缓解。对于其他人来说，用阿片类药物治疗疼痛可能会导致依赖性和成瘾。个人的性别是决定阿片类药物减轻疼痛的有效性和滥用可能性的主要因素之一。在人类和啮齿类动物的文献中，均已证明在施用阿片类药物后，雄性比雌性体验到更强的镇痛效果。相比之下，吗啡对女性的有益作用比对男性大得多。寻找性别对吗啡引起的镇痛和奖赏的不同影响的共同机制一直很困难。然而，最近的证据表明吗啡有效性的一个关键组成部分涉及通过先天免疫系统的模式识别受体 Toll 样受体 (TLR) 4 直接激活大脑中的小胶质细胞。吗啡诱导的大脑中小胶质细胞的激活启动了促炎细胞因子的释放显着增加阿片类药物诱导的奖赏、耐受性和依赖性，同时降低阿片类药物的镇痛作用。因此，我们假设吗啡诱导的小胶质细胞激活在女性中显着高于男性，并且这种神经胶质激活可能是性别对吗啡诱导的镇痛和奖赏产生不同影响的潜在机制。该提案的主要目标有三个： 1) 了解吗啡治疗后免疫激活的基本性别差异； 2）了解吗啡诱导的神经胶质激活在吗啡诱导的镇痛和滥用倾向的性别差异中的潜在作用； 3）确定小胶质细胞的具体作用并开始确定潜在机制。 公共卫生相关性：个体性别是决定阿片类镇痛效果的主要因素。该提案的结果将有助于深入了解免疫系统在吗啡有效性中所起的作用，以及两性之间药物滥用的可能性。了解药物对男性和女性的不同影响是寻求个性化医疗的第一步。