Opioid analgesics represent a critical treatment for chronic pain in the analgesic ladder of the World Health Organization. However, their use can result in a number of unwanted side-effects including incomplete efficacy, constipation, physical dependence, and overdose liability. Cannabinoids enhance the pain-relieving effects of opioids in preclinical studies and dampen unwanted side-effects resulting from excessive opioid intake. We recently reported that a CB1 positive allosteric modulator (PAM) exhibits antinociceptive efficacy in models of pathological pain and lacks the adverse side effects of direct CB1 receptor activation. In the present study, we evaluated whether a CB1 PAM would enhance morphine's therapeutic efficacy in an animal model of chemotherapy-induced neuropathic pain and characterized its impact on unwanted side-effects associated with chronic opioid administration. In paclitaxel-treated mice, both the CB1 PAM GAT211 and the opioid analgesic morphine reduced paclitaxel-induced behavioral hypersensitivities to mechanical and cold stimulation in a dose-dependent manner. Isobolographic analysis revealed that combinations of GAT211 and morphine resulted in anti-allodynic synergism. In paclitaxel-treated mice, a sub-threshold dose of GAT211 prevented the development of tolerance to the anti-allodynic effects of morphine over 20 days of once daily dosing. However, GAT211 did not reliably alter somatic withdrawal signs (i.e., jumps, paw tremors) in morphine-dependent neuropathic mice challenged with naloxone. In otherwise naïve mice, GAT211 also prolonged antinociceptive efficacy of morphine in the tail-flick test and reduced the overall right-ward shift in the ED50 for morphine to produce antinociception in the tail-flick test, consistent with attenuation of morphine tolerance. Pretreatment with GAT211 did not alter somatic signs of μ opioid receptor dependence in mice rendered dependent upon morphine via subcutaneous implantation of a morphine pellet. Moreover, GAT211 did not reliably alter μ-opioid receptor-mediated reward as measured by conditioned place preference to morphine. Our results suggest that a CB1 PAM may be beneficial in enhancing and prolonging the therapeutic properties of opioids while potentially sparing unwanted side-effects (e.g., tolerance) that occur with repeated opioid treatment.

中文翻译：

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CB1大麻素受体信号的正变构调制增强了吗啡的抗伤害感受能力，并减轻了吗啡的耐受性，而没有增强吗啡诱导的依赖性或报酬。

阿片类镇痛药是世界卫生组织镇痛阶梯中治疗慢性疼痛的关键方法。但是，它们的使用可能会导致许多不良副作用，包括功效不完全，便秘，身体依赖性和过量用药。大麻素在临床前研究中增强了阿片类药物的止痛作用，并减轻了因过量摄入阿片类药物而引起的不良副作用。我们最近报道，CB1阳性变构调节剂（PAM）在病理性疼痛模型中显示出抗伤害感受的功效，并且缺乏直接CB1受体激活的不利副作用。在本研究中，我们评估了CB1 PAM是否会增强吗啡' 在化学疗法诱发的神经性疼痛的动物模型中具有良好的治疗功效，并表征了其对与慢性阿片类药物相关的不良副作用的影响。在紫杉醇治疗的小鼠中，CB1 PAM GAT211和阿片类镇痛吗啡均以剂量依赖的方式降低了紫杉醇对机械和冷刺激的行为超敏反应。等效线描记法分析表明，GAT211和吗啡的组合可导致抗异常性增效作用。在紫杉醇治疗的小鼠中，亚阈值剂量的GAT211阻止了每日一次给药20天后对吗啡的抗痛觉过敏作用的耐受性的发展。但是，在用纳洛酮攻击的吗啡依赖性神经病小鼠中，GAT211不能可靠地改变体细胞戒断症状（即跳跃，爪震颤）。在其他天真的老鼠中，GAT211还延长了吗啡在甩尾试验中的镇痛效果，并降低了吗啡在ED50中的总体右移，从而在甩尾试验中产生了镇痛作用，这与吗啡耐受性的降低相一致。用GAT211预处理不会改变通过皮下植入吗啡丸而依赖吗啡的小鼠中μ阿片受体依赖性的体征。此外，GAT211不能可靠地改变μ阿片受体介导的奖励，这是通过对吗啡的条件性位置偏爱来衡量的。我们的结果表明，CB1 PAM可能有助于增强和延长阿片类药物的治疗性能，同时潜在地避免重复阿片类药物治疗产生的不良副作用（例如耐受性）。