Immune Function and Sex Differences in Morphine Analgesia and Reward

描述(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治疗疼痛的最有效方法，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和成瘾。一个人的性别是决定阿片类药物对减轻疼痛的有效性和可能的滥用责任的一个主要因素。在人类和啮齿动物的文献中，都已经证明了在给予阿片类药物后，雄性比雌性体验到更强的止痛。相比之下，吗啡的有益作用在女性身上要比男性强得多。寻找性别对吗啡诱导的止痛和奖赏有如此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是通过先天免疫系统的模式识别受体Toll样受体(TLR4)直接激活脑内的小胶质细胞。这种由吗啡诱导的脑内小胶质细胞的激活启动了促炎细胞因子的释放，从而显著增加了阿片类药物诱导的奖赏、耐受和依赖，同时减少了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的激活在女性中显著高于男性，这种神经胶质细胞的激活可能是性别对吗啡诱导的镇痛和奖赏的不同影响的潜在机制。这项建议的主要目的有三个：1)了解吗啡治疗后免疫激活的基本性别差异；2)了解吗啡诱导的胶质细胞激活在吗啡诱导的镇痛和滥用倾向中的性别差异中的潜在作用；3)确定小胶质细胞的特定作用并开始确定可能的机制。

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.