虽然阿片类药物危机有理由占据新闻头条,急诊室看到成千上万的探视是另一个原因:大麻素毒性。部分原因是廉价且极其有效的合成大麻素的传播,每年都会导致严重的神经和心血管并发症甚至死亡。虽然纳洛酮可以逆转阿片类药物过量,大麻毒性没有类似的治疗方法。没有解药,医生依靠镇静剂,有自己的风险,或者“等着治疗这些病人”。我们已经证明,典型的合成\'设计师\'大麻素是高度有效的CB1受体激动剂,因此,竞争性拮抗剂可能难以迅速逆转由于合成大麻素的过量。负变构调节剂(NAMs)具有减弱合成大麻素的作用而不必直接竞争结合的潜力。我们测试了一组CB1NAM在内源性大麻素信号传导的神经元模型中以及在体内的体外逆转经典合成设计者大麻素JWH018的作用的能力。我们测试了ABD1085,RTICBM189和PSNCBAM1在内源性海马神经元中的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阻断/逆转了JWH018,尽管一些被证明比其他化合物更有效。然后我们测试了这些化合物是否可以在体内阻断JWH018的作用,使用小鼠的伤害感受测试。我们发现这些化合物中只有两种-RTICBM189和PSNCBAM1-在预先应用时阻断了JWH018。化合物的体外效力不能预测其体内效力。PSNCBAM1被证明是更有效的化合物,并且在随后应用时也逆转了JWH018的作用,更接近地模仿过量情况的条件。最后,我们发现PSNCBAM1在慢性JWH018治疗后未引起停药.总之,CB1NAM可以,原则上,逆转经典合成设计师大麻素JWH018在体外和体内的作用,不诱导退出。这些发现表明了一种新的药理学方法,最终提供了一种对抗大麻素毒性的工具。
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.