Immune Function and Sex Differences in Morphine Analgesia and Reward

描述（由申请人提供）：阿片类药物，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。对其他人来说，用阿片类药物治疗疼痛可能会导致依赖和成瘾。一个人的性别是确定阿片类药物减轻疼痛的有效性和滥用可能性的一个主要因素。在人类和啮齿类动物文献中，已证明阿片类药物给药后雄性动物的镇痛作用大于雌性动物。相比之下，吗啡的奖励属性在女性中比男性大得多。寻找一个共同的机制，性别对吗啡诱导的镇痛和奖励的不同影响一直很困难。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。这种吗啡诱导的脑中小胶质细胞的激活启动促炎细胞因子的释放，其显著增加阿片类药物诱导的奖赏、耐受性和依赖性，同时减少阿片类药物镇痛。因此，我们假设，吗啡诱导的小胶质细胞的激活是显着更大的女性相比，男性，这种胶质细胞的激活可能是一个潜在的机制，性别差异对吗啡诱导的镇痛和奖励的影响。本提案的主要目标有三个方面：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细胞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）建立小胶质细胞的特定作用，并开始确定潜在机制。

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.