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，但它们并不能充分缓解所有人的疼痛。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。一个人的性别是决定阿片类药物在减轻疼痛和潜在滥用责任方面的有效性的一个主要因素。在人类和啮齿动物的文献中，已经证明雄性在服用阿片类药物后比雌性经历更大的镇痛。相比之下，吗啡对女性的奖励作用要比男性大得多。寻找一种共同的机制来解释性别对吗啡诱导的镇痛和奖励的不同影响是很困难的。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。吗啡诱导的大脑小胶质细胞的激活启动了促炎细胞因子的释放，这些细胞因子显著增加阿片类药物诱导的奖励、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在女性中明显大于男性，这种胶质细胞的激活可能是性别对吗啡诱导的镇痛和奖励的不同影响的潜在机制。这项建议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激活在吗啡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.