While the opioid crisis has justifiably occupied news headlines, emergency rooms are seeing many thousands of visits for another cause: cannabinoid toxicity. This is partly due to the spread of cheap and extremely potent synthetic cannabinoids that can cause serious neurological and cardiovascular complications—and deaths—every year. While an opioid overdose can be reversed by naloxone, there is no analogous treatment for cannabis toxicity. Without an antidote, doctors rely on sedatives, with their own risks, or ‘waiting it out’ to treat these patients. We have shown that the canonical synthetic ‘designer’ cannabinoids are highly potent CB1 receptor agonists and, as a result, competitive antagonists may struggle to rapidly reverse an overdose due to synthetic cannabinoids. Negative allosteric modulators (NAMs) have the potential to attenuate the effects of synthetic cannabinoids without having to directly compete for binding. We tested a group of CB1 NAMs for their ability to reverse the effects of the canonical synthetic designer cannabinoid JWH018 in vitro in a neuronal model of endogenous cannabinoid signaling and also in vivo. We tested ABD1085, RTICBM189, and PSNCBAM1 in autaptic hippocampal neurons that endogenously express a retrograde CB1-dependent circuit that inhibits neurotransmission. We found that all of these compounds blocked/reversed JWH018, though some proved more potent than others. We then tested whether these compounds could block the effects of JWH018 in vivo, using a test of nociception in mice. We found that only two of these compounds—RTICBM189 and PSNCBAM1—blocked JWH018 when applied in advance. The in vitro potency of a compound did not predict its in vivo potency. PSNCBAM1 proved to be the more potent of the compounds and also reversed the effects of JWH018 when applied afterward, a condition that more closely mimics an overdose situation. Lastly, we found that PSNCBAM1 did not elicit withdrawal after chronic JWH018 treatment. In summary, CB1 NAMs can, in principle, reverse the effects of the canonical synthetic designer cannabinoid JWH018 both in vitro and in vivo, without inducing withdrawal. These findings suggest a novel pharmacological approach to at last provide a tool to counter cannabinoid toxicity.

中文翻译：

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CB1 受体负变构调节剂作为逆转大麻素毒性的潜在工具

虽然阿片类药物危机理所当然地占据了新闻头条，但急诊室却因另一个原因而导致数千人就诊：大麻素中毒。部分原因是廉价且极其有效的合成大麻素的传播，这些大麻素每年都会导致严重的神经和心血管并发症以及死亡。虽然纳洛酮可以逆转阿片类药物过量，但对于大麻毒性没有类似的治疗方法。在没有解毒剂的情况下，医生只能依靠镇静剂来治疗这些患者，这也有其自身的风险，或者“等待”。我们已经证明，经典的合成“设计”大麻素是高效的 CB1 受体激动剂，因此，竞争性拮抗剂可能难以快速逆转合成大麻素造成的过量用药。负变构调节剂（NAM）有可能减弱合成大麻素的作用，而无需直接竞争结合。我们测试了一组 CB1 NAM 在内源性大麻素信号传导的神经元模型中以及在体内逆转经典合成设计大麻素 JWH018 的影响的能力。我们在自体海马神经元中测试了 ABD1085、RTICBM189 和 PSNCBAM1，这些神经元内源性表达抑制神经传递的逆行 CB1 依赖性回路。我们发现所有这些化合物都能阻断/逆转 JWH018，尽管其中一些化合物比其他化合物更有效。然后，我们通过小鼠伤害感受测试来测试这些化合物是否可以在体内阻断 JWH018 的作用。我们发现，这些化合物中只有两种——RTICBM189 和 PSNCBAM1——在提前施用时会阻断 JWH018。化合物的体外效力并不能预测其体内效力。 PSNCBAM1 被证明是这些化合物中更有效的，并且在随后使用时还逆转了 JWH018 的作用，这种情况更接近于服药过量的情况。最后，我们发现 PSNCBAM1 在长期 JWH018 治疗后不会引起戒断。总之，CB1 NAM 原则上可以在体外和体内逆转经典合成大麻素 JWH018 的作用，而不会引起戒断。这些发现表明一种新的药理学方法最终提供了对抗大麻素毒性的工具。