Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine
Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine
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DOI：
10.1523/jneurosci.2906-16.2017
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发表时间：
2017-03-22
影响因子：
5.3
通讯作者：
Murphy, Anne Z.
中科院分区：
文献类型：
--
作者：
Doyle, Hillary H.;Eidson, Lori N.;Murphy, Anne Z.
虽然吗啡仍然是缓解严重或持续疼痛的主要药物，但临床前和临床研究表明，女性需要比男性多两到三倍的吗啡才能产生类似的镇痛水平。除了与神经元μ-阿片受体结合外，吗啡还与主要位于小胶质细胞上的先天免疫受体toll样受体4（TLR 4）结合。吗啡对TLR 4的作用启动了直接对抗吗啡镇痛作用的神经炎症反应。在这里，我们测试的假设，即在女性中观察到的吗啡的衰减反应是导水管周围灰质（PAG），一个中央位点介导的吗啡的镇痛作用的小胶质细胞激活增加的结果。我们报告说，而没有整体的性别差异，小胶质细胞的密度在PAG内的男性或女性大鼠，小胶质细胞表现出更多的“激活”的表型在女性在基线，与激活程度的吗啡半数最大抗伤害剂量（ED 50）值的显着预测。与男性相比，用LPS引发小胶质细胞可诱导女性PAG中更大的小胶质细胞活化，并伴有IL-1 β转录水平增加和吗啡剂量反应曲线显着右移。用（+）-纳洛酮阻断吗啡与PAG TLR 4的结合显著增强了雌性中的吗啡镇痛作用，因此未观察到ED 50的性别差异。这些结果表明，PAG小胶质细胞在基础和LPS诱导的激活中是性二态的，并有助于吗啡在大鼠中的性二态效应。
Although morphine remains the primary drug prescribed for alleviation of severe or persistent pain, both preclinical and clinical studies have shown that females require two to three times more morphine than males to produce comparable levels of analgesia. In addition to binding to the neuronal mu-opioid receptor, morphine binds to the innate immune receptor toll-like receptor 4 (TLR4) localized primarily on microglia. Morphine action at TLR4 initiates a neuroinflammatory response that directly opposes the analgesic effects of morphine. Here, we test the hypothesis that the attenuated response to morphine observed in females is the result of increased microglia activation in the periaqueductal gray (PAG), a central locus mediating the antinociceptive effects of morphine. We report that, whereas no overall sex differences in the density of microglia were noted within the PAG of male or female rats, microglia exhibited a more "activated" phenotype in females at baseline, with the degree of activation a significant predictor of morphine half-maximal antinociceptive dose (ED50) values. Priming microglia with LPS induced greater microglia activation in the PAG of females compared with males and was accompanied by increased transcription levels of IL-1 beta and a significant rightward shift in the morphine dose-response curve. Blockade of morphine binding to PAG TLR4 with (+)-naloxone potentiated morphine antinociception significantly in females such that no sex differences in ED50 were observed. These results demonstrate that PAG microglia are sexually dimorphic in both basal and LPS-induced activation and contribute to the sexually dimorphic effects of morphine in the rat.