Program in Neuroscience, Indiana University, Bloomington, IN, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
Neuropharmacology. 2024 Oct 1;257:110052. doi: 10.1016/j.neuropharm.2024.110052. Epub 2024 Jun 25.
The direct blockade of CB cannabinoid receptors produces therapeutic effects as well as adverse side-effects that limit their clinical potential. CB negative allosteric modulators (NAMs) represent an indirect approach to decrease the affinity and/or efficacy of orthosteric cannabinoid ligands or endocannabinoids at CB. We recently reported that GAT358, a CB-NAM, blocked opioid-induced mesocorticolimbic dopamine release and reward via a CB-allosteric mechanism of action. Whether a CB-NAM dampens opioid-mediated therapeutic effects such as analgesia or alters other unwanted opioid side-effects remain unknown. Here, we characterized the effects of GAT358 on nociceptive behaviors in the presence and absence of morphine in male rats. We examined the impact of GAT358 on formalin-evoked pain behavior and Fos protein expression, a marker of neuronal activation, in the lumbar spinal cord. We also assessed the impact of GAT358 on morphine-induced slowing of colonic transit, tolerance, and withdrawal behaviors in male mice. GAT358 attenuated morphine antinociceptive tolerance without blocking acute antinociception and reduced morphine-induced slowing of colonic motility without impacting fecal boli production. GAT358 also produced antinociception in the presence and absence of morphine in the formalin model of inflammatory nociception and reduced the number of formalin-evoked Fos protein-like immunoreactive cells in the lumbar spinal cord. Finally, GAT358 mitigated the somatic signs of naloxone-precipitated, but not spontaneous, opioid withdrawal following chronic morphine dosing. Our results support the therapeutic potential of CB-NAMs as novel drug candidates aimed at preserving opioid-mediated analgesia while preventing their unwanted side-effects. Our studies also uncover previously unrecognized antinociceptive properties associated with an arrestin-biased CB-NAM.
大麻素 CB 受体的直接阻断会产生治疗效果和不良反应，从而限制了其临床应用潜力。大麻素 CB 负变构调节剂（NAMs）代表了一种间接方法，可以降低 CB 型正位大麻素配体或内源性大麻素的亲和力和/或效力。我们最近报道，GAT358 是一种 CB-NAM，通过 CB 变构作用机制阻断阿片类药物诱导的中皮质边缘多巴胺释放和奖赏。CB-NAM 是否会抑制阿片类药物介导的治疗效果（如镇痛）或改变其他不良的阿片类药物副作用尚不清楚。在这里，我们在雄性大鼠中研究了 GAT358 在吗啡存在和不存在的情况下对伤害性感受行为的影响。我们研究了 GAT358 对福尔马林诱发的疼痛行为和 Fos 蛋白表达的影响，Fos 蛋白是神经元激活的标志物，检测部位是腰脊髓。我们还评估了 GAT358 对雄性小鼠吗啡引起的结肠转运减慢、耐受和戒断行为的影响。GAT358 减弱了吗啡的镇痛耐受而不阻断急性镇痛作用，并减少了吗啡引起的结肠运动减慢而不影响粪便产生。GAT358 在福尔马林诱导的炎症性伤害感受模型中也产生了镇痛作用，并减少了腰脊髓中福尔马林诱导的 Fos 蛋白样免疫反应细胞的数量。最后，GAT358 减轻了慢性吗啡给药后纳洛酮诱发的、但不是自发的阿片类药物戒断的躯体症状。我们的研究结果支持 CB-NAMs 作为新型候选药物的治疗潜力，旨在保留阿片类药物介导的镇痛作用，同时防止其不良副作用。我们的研究还揭示了与一种偏向 arrestin 的 CB-NAM 相关的以前未被认识到的镇痛特性。
