Zhang Hong, Lipinski Austin A, Liktor-Busa Erika, Smith Angela F, Moutal Aubin, Khanna Rajesh, Langlais Paul R, Largent-Milnes Tally M, Vanderah Todd W
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States.
Department of Medicine, Division of Endocrinology, College of Medicine, University of Arizona, Tucson, AZ, United States.
Front Pharmacol. 2021 Apr 16;12:632757. doi: 10.3389/fphar.2021.632757. eCollection 2021.
The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry. Studies here using proteomic analysis and quantitative real-time PCR (qRT-PCR) found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; three of these proteins or genes (PLCγ2, ABHD6, and CB2R) were significantly affected after repeated morphine exposure (CB2R was only detected by qRT-PCR but not proteomics). We also identified that repeated morphine treatment does not alter either anandamide (AEA) or 2-arachidonoylglycerol (2-AG) levels in the VTA compared to saline treatment; however, there may be diminished levels of anandamide (AEA) production in the VTA 4 h after a single morphine injection in both chronic saline and morphine pretreated cohorts. Treating the animals with an inhibitor of 2-AG degradation significantly decreased repeated opioid rewarding behavior. Taken together, our studies reveal a potential influence of sustained opioids on the endocannabinoid system in the VTA, suggesting that the endogenous cannabinoid system may participate in the opioid-induced reward.
阿片类药物的治疗效用因其诱导奖赏行为的能力而降低，这种奖赏行为可能导致阿片类药物使用障碍。最近，内源性大麻素系统已成为阿片类奖赏研究中的一个热门话题，但关于反复暴露于阿片类药物如何影响中脑边缘奖赏回路中的内源性大麻素系统，人们了解得相对较少。在本研究中，我们调查了持续给予吗啡如何调节Sprague Dawley大鼠腹侧被盖区（VTA）的内源性大麻素系统，VTA是中脑边缘奖赏回路中的一个关键区域。本研究使用蛋白质组学分析和定量实时PCR（qRT-PCR）发现，VTA表达32种与内源性大麻素系统相关的不同蛋白质或基因；反复给予吗啡后，其中三种蛋白质或基因（PLCγ2、ABHD6和CB2R）受到显著影响（CB2R仅通过qRT-PCR检测到，蛋白质组学未检测到）。我们还发现，与生理盐水处理相比，反复给予吗啡处理不会改变VTA中花生四烯酸乙醇胺（AEA）或2-花生四烯酸甘油酯（2-AG）的水平；然而，在慢性生理盐水和吗啡预处理组中，单次注射吗啡后4小时，VTA中花生四烯酸乙醇胺（AEA）的生成水平可能会降低。用2-AG降解抑制剂处理动物可显著降低反复给予阿片类药物的奖赏行为。综上所述，我们的研究揭示了持续使用阿片类药物对VTA内源性大麻素系统的潜在影响，表明内源性大麻素系统可能参与了阿片类药物诱导的奖赏。
