1 Department of Anesthesiology and Perioperative Medicine, Penn State University College of Medicine, Hershey, PA, USA.
2 Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA.
Mol Pain. 2017 Jan-Dec;13:1744806917728227. doi: 10.1177/1744806917728227.
The cannabinoid 1 receptor and cannabinoid 2 receptor can both be targeted in the treatment of pain; yet, they have some important differences. Cannabinoid 1 receptor is expressed at high levels in the central nervous system, whereas cannabinoid 2 receptor is found predominantly, although not exclusively, outside the central nervous system. The objective of this study was to investigate potential interactions between cannabinoid 2 receptor and the mu-opioid receptor in pathological pain. The low level of adverse side effects and lack of tolerance for cannabinoid 2 receptor agonists are attractive pharmacotherapeutic traits. This study assessed the anti-nociceptive effects of a selective cannabinoid 2 receptor agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with morphine. JWH-133 produces dose-dependent anti-nociception during both the acute and inflammatory phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. After eleven once-daily injections of 1 mg/JWH-133, no tolerance was observed in the formalin test. Cross-tolerance for the anti-nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant cannabinoid 2 receptor and mu-opioid receptor interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH-133 response in both phases of the formalin test compared to vehicle-treated morphine-naïve animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine, suggesting opioid and cannabinoid 2 receptor cross-tolerance is unidirectional. However, preliminary data suggest co-administration of JWH-133 with morphine modestly attenuates morphine tolerance. Isobolographic analysis revealed that co-administration of JWH-133 and morphine has an additive effect on anti-nociception in the formalin test. Overall these findings show that cannabinoid 2 receptor may functionally interact with mu-opioid receptor to modulate anti-nociception in the formalin test.
大麻素 1 型受体和大麻素 2 型受体均可用于治疗疼痛；然而，它们存在一些重要差异。大麻素 1 型受体在中枢神经系统中表达水平较高，而大麻素 2 型受体主要存在于中枢神经系统之外，但并非完全不存在于中枢神经系统之外。本研究旨在探讨大麻素 2 型受体与μ-阿片受体在病理性疼痛中的潜在相互作用。大麻素 2 型受体激动剂的不良反应发生率低且不易产生耐受性，这是其具有吸引力的药理学特征。本研究使用福尔马林测试评估了炎症性疼痛模型中小鼠中选择性大麻素 2 型受体激动剂（JWH-133）的抗伤害作用。此外，我们还研究了 JWH-133 与吗啡相互作用的几种方式。JWH-133 在福尔马林测试的急性和炎症期均产生剂量依赖性的抗伤害作用。这在雄性和雌性小鼠中均观察到。然而，JWH-133 的最大有效剂量（1mg/kg）不会引起躯体戒断症状、运动障碍或体温过低。在接受 11 次 1mg/JWH-133 的每日注射后，在福尔马林测试中未观察到耐受。评估 JWH-133 和吗啡的抗伤害作用的交叉耐受，以深入了解生理相关的大麻素 2 型受体和μ-阿片受体相互作用。对吗啡作用产生耐受的小鼠在福尔马林测试的两个阶段中对 JWH-133 的反应均低于接受载体处理的吗啡未处理动物。然而，重复每日 JWH-133 给药不会导致吗啡交叉耐受，这表明阿片类药物和大麻素 2 型受体交叉耐受是单向的。然而，初步数据表明，JWH-133 与吗啡联合给药可适度减轻吗啡耐受。等辐射分析显示，JWH-133 和吗啡联合给药对福尔马林测试中的抗伤害作用具有相加作用。总体而言，这些发现表明大麻素 2 型受体可能与μ-阿片受体在功能上相互作用，以调节福尔马林测试中的抗伤害作用。
