Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed male and female mice to consume ∆9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Mice stably consumed these gelatins over 3 weeks, with detectable serum levels. Using a real-time gelatin measurement system, we observed that mice consumed gelatin throughout the light and dark cycles, with animals consuming less THC-gelatin than the other gelatin groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after 1 week while THC or CBD reduced allodynia over three weeks. Hyperalgesia gradually developed after sciatic nerve injury, and by the last day of testing, THC significantly reduced hyperalgesia, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine. This study demonstrates that mice voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids provide long-term relief of chronic pain states. In addition, ultrasonic clicks may objectively represent mouse pain status and could be integrated into future pain models.

中文翻译：

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口服大麻素可以长期缓解慢性神经性疼痛小鼠模型的异常性疼痛。


慢性疼痛影响着相当大比例的美国人口，而阿片类药物等现有止痛药物存在缺点，无法长期使用。大麻素在治疗疼痛方面显示出前景，但在临床前模型中实施大麻素长期治疗疼痛一直具有挑战性。我们开发了一种自愿的明胶口服自我给药模式，允许雄性和雌性小鼠随意摄入 9-四氢大麻酚、大麻二酚或吗啡。小鼠在三周内稳定地消耗这些明胶，并可检测到血清水平。使用实时明胶测量系统，我们观察到小鼠在整个光照和黑暗周期中消耗明胶，其中与其他明胶组相比，动物消耗的 THC 明胶较少。在慢性神经性坐骨神经损伤模型中，食用所有三种明胶均减少了异常性疼痛，但 1 周后出现了对吗啡的耐受性，而 THC 或 CBD 在三周内减少了异常性疼痛。坐骨神经损伤后痛觉过敏逐渐出现，到测试的最后一天，THC 显着减轻痛觉过敏，具有 CBD 的趋势效应，而吗啡没有效应。在整个实验过程中记录了小鼠的发声，坐骨神经损伤后，小鼠的超声波、宽带喀哒声大幅增加，而 THC、CBD 和吗啡可以逆转这种情况。这项研究表明，小鼠通过明胶自愿消耗大麻素和阿片类药物，并且大麻素可以长期缓解慢性疼痛状态。此外，超声波点击可以客观地代表小鼠的疼痛状态，并且可以集成到未来的疼痛模型中。