Sex differences in morphine-induced trafficking of mu-opioid and corticotropin-releasing factor receptors in locus coeruleus neurons
Sex differences in morphine-induced trafficking of mu-opioid and corticotropin-releasing factor receptors in locus coeruleus neurons
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DOI：
10.1016/j.brainres.2018.11.001
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发表时间：
2019-03-01
期刊：
影响因子：
2.9
通讯作者：
Van Bockstaele, Elisabeth J.
中科院分区：
文献类型：
--
作者：
Enman, Nicole M.;Reyes, Beverly A. S.;Van Bockstaele, Elisabeth J.
蓝斑（LC）-去甲肾上腺素（NE）系统是内源性阿片类药物和应激系统交叉调节应激反应的关键核。长期服用吗啡后，雄性大鼠的 LC 神经元对压力变得敏感。性别是否决定了阿片类药物诱导的可塑性模式尚未得到证实。描述慢性阿片类药物产生的神经生物学适应将增强我们对阿片类药物依赖个体的压力脆弱性的理解，并可能揭示压力如何对成瘾恢复产生负面影响。在本研究中，使用免疫电子显微镜研究了长期吗啡对雄性和雌性大鼠LC中μ阿片类药物（MOR）和CRF受体（CRFR）亚细胞分布的影响。结果显示，与安慰剂治疗的男性相比，安慰剂治疗的女性表现出更高的 MOR 和 CRFR 细胞质分布比。慢性吗啡暴露诱导雄性 LC 神经元中 MOR 免疫金银颗粒的分布选择性从质膜转移到细胞质。有趣的是，慢性吗啡暴露诱导 CRFR 募集到雄性和雌性 LC 神经元的质膜上。这些发现提供了一种潜在机制，通过增加 LC 神经元中 CRFR 的表面可用性，长期使用阿片类药物会增加男性和女性的应激脆弱性。然而，我们的结果也支持这样的观点，即细胞对慢性阿片类药物的适应因性别而异，因为仅在男性 LC 神经元中观察到吗啡暴露后 MOR 的重新分布。
The locus coeruleus (LC)-norepinephrine (NE) system is a key nucleus in which endogenous opioid and stress systems intersect to regulate the stress response. LC neurons of male rats become sensitized to stress following chronic morphine administration. Whether sex dictates this pattern of opioid-induced plasticity has not been demonstrated. Delineating the neurobiological adaptations produced by chronic opioids will enhance our understanding of stress vulnerability in opioid-dependent individuals, and may reveal how stress negatively impacts addiction recovery. In the present study, the effect of chronic morphine on the subcellular distribution of mu-opioid (MOR) and CRF receptors (CRFR) was investigated in the LC of male and female rats using immunoelectron microscopy. Results showed that placebo-treated females exhibited higher MOR and CRFR cytoplasmic distribution ratio when compared to placebo-treated males. Chronic morphine exposure induced a shift in the distribution of MOR immunogold-silver particles from the plasma membrane to the cytoplasm selectively in male LC neurons. Interestingly, chronic morphine exposure induced CRFR recruitment to the plasma membrane of both male and female LC neurons. These findings provide a potential mechanism by which chronic opioid administration increases stress vulnerability in males and females via an increase in surface availability of CRFR in LC neurons. However, our results also support the notion that cellular adaptations to chronic opioids differ across the sexes as redistribution of MOR following morphine exposure was only observed in male LC neurons.