Reichenbach Zachary W, DiMattio Kelly, Rajakaruna Suren, Ambrose David, Cornwell William D, Tallarida Ronald J, Rogers Thomas, Liu-Chen Lee-Yuan, Tuma Ronald F, Ward Sara Jane
Center for Substance Abuse Research (CSAR), Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.
Department of Gastroenterology and Hepatology, Temple University Hospital, Philadelphia, PA, United States.
Front Pharmacol. 2022 Apr 21;13:803331. doi: 10.3389/fphar.2022.803331. eCollection 2022.
Acutely, non-selective cannabinoid (CB) agonists have been shown to increase morphine antinociceptive effects, and we and others have also demonstrated that non-selective CB agonists attenuate morphine antinociceptive tolerance. Activation of cannabinoid CB2 receptors reverses allodynia and hyperalgesia in models of chronic pain, and co-administration of morphine with CB2 receptor selective agonists has been shown to be synergistic. CB2 receptor activation has also been shown to reduce morphine-induced hyperalgesia in rodents, an effect attributed to CB2 receptor modulation of inflammation. In the present set of experiments, we tested both the acute and chronic interactions between morphine and the CB2 receptor selective agonist O-1966 treatments on antinociception and antinociceptive tolerance in C57Bl6 mice. Co-administration of morphine and O-1966 was tested under three dosing regimens: simultaneous administration, morphine pre-treated with O-1966, and O-1966 pre-treated with morphine. The effects of O-1966 on mu-opioid receptor binding were determined using [3H]DAMGO and [S]GTPγS binding assays, and these interactions were further examined by FRET analysis linked to flow cytometry. Results yielded surprising evidence of interactions between the CB2 receptor selective agonist O-1966 and morphine that were dependent upon the order of administration. When O-1966 was administered prior to or simultaneous with morphine, morphine antinociception was attenuated and antinociceptive tolerance was exacerbated. When O-1966 was administered following morphine, morphine antinociception was not affected and antinociceptive tolerance was attenuated. The [S]GTPγS results suggest that O-1966 interrupts functional activity of morphine at the mu-opioid receptor, leading to decreased potency of morphine to produce acute thermal antinociceptive effects and potentiation of morphine antinociceptive tolerance. However, O-1966 administered after morphine blocked morphine hyperalgesia and led to an attenuation of morphine tolerance, perhaps due to well-documented anti-inflammatory effects of CB2 receptor agonism.
急性情况下，已证实非选择性大麻素（CB）激动剂可增强吗啡的镇痛作用，并且我们和其他人也已证明非选择性CB激动剂可减轻吗啡镇痛耐受性。在慢性疼痛模型中，大麻素CB2受体的激活可逆转异常性疼痛和痛觉过敏，并且已证明吗啡与CB2受体选择性激动剂联合给药具有协同作用。CB2受体激活还已证明可减轻啮齿动物中吗啡诱导的痛觉过敏，这一作用归因于CB2受体对炎症的调节。在本系列实验中，我们测试了吗啡与CB2受体选择性激动剂O-1966治疗在C57Bl6小鼠中对镇痛和镇痛耐受性的急性和慢性相互作用。在三种给药方案下测试了吗啡和O-1966的联合给药：同时给药、用O-1966预处理吗啡以及用吗啡预处理O-1966。使用[3H]DAMGO和[S]GTPγS结合试验确定O-1966对μ-阿片受体结合的影响，并通过与流式细胞术相关的FRET分析进一步研究这些相互作用。结果产生了令人惊讶的证据，表明CB2受体选择性激动剂O-1966与吗啡之间的相互作用取决于给药顺序。当在吗啡之前或同时给予O-1966时，吗啡镇痛作用减弱且镇痛耐受性加剧。当在吗啡之后给予O-1966时，吗啡镇痛作用不受影响且镇痛耐受性减弱。[S]GTPγS结果表明，O-1966中断了吗啡在μ-阿片受体处的功能活性，导致吗啡产生急性热镇痛作用的效力降低以及吗啡镇痛耐受性增强。然而，在吗啡之后给予O-1966可阻断吗啡诱导的痛觉过敏并导致吗啡耐受性减弱，这可能是由于CB2受体激动作用已充分记录的抗炎作用。
