Wilson Adrianne R, Maher Lauren, Morgan Michael M
Department of Neuroscience, Washington State University Vancouver, 14204 NE Salmon Creek Avenue, Vancouver, WA 98686, USA.
Neuropharmacology. 2008 Dec;55(7):1219-25. doi: 10.1016/j.neuropharm.2008.07.038. Epub 2008 Aug 5.
Cannabinoids and opiates inhibit pain, in part, by activating the periaqueductal gray (PAG). Evidence suggests this activation occurs through distinct mechanisms. If the antinociceptive mechanisms are distinct, then cross-tolerance between opioids and cannabinoids should not develop. This hypothesis was tested by measuring the antinociceptive effect of microinjecting morphine into the ventrolateral PAG of rats pretreated with the cannabinoid HU-210 for two days. Male Sprague-Dawley rats were injected twice a day for two days with vehicle (0.4 microL), morphine (5 microg/0.4 microL), HU-210 (5 microg/0.4 microL), or morphine combined with HU-210 into the ventrolateral PAG. Repeated injections of morphine caused a rightward shift in the morphine dose-response curve on Day 3 (i.e., tolerance developed). No tolerance was evident in rats pretreated with morphine combined with HU-210. In rats pretreated with HU-210 alone, morphine antinociception was enhanced. This enhancement was blocked by pretreating rats with the cannabinoid receptor antagonist AM-251, and it also disappeared when rats were tested one week later. Acute microinjection of HU-210 into the PAG antagonized morphine antinociception, suggesting that HU-210-induced enhancement of morphine antinociception is a compensatory response. As hypothesized, there was no evidence of cross-tolerance between morphine and HU-210. In fact, cannabinoid pretreatment enhanced the antinociceptive effect of microinjecting morphine into the ventrolateral PAG. These findings suggest that alternating opioid and cannabinoid treatment could be therapeutically advantageous by preventing the development of tolerance and enhancing morphine antinociception.
大麻素和阿片类药物部分通过激活中脑导水管周围灰质（PAG）来抑制疼痛。有证据表明这种激活是通过不同机制发生的。如果抗伤害感受机制不同，那么阿片类药物和大麻素之间不应产生交叉耐受性。通过测量向预先用大麻素HU - 210处理两天的大鼠腹外侧PAG微量注射吗啡的抗伤害感受作用，对这一假设进行了检验。雄性Sprague - Dawley大鼠每天注射两次，持续两天，分别注射溶媒（0.4微升）、吗啡（5微克/0.4微升）、HU - 210（5微克/0.4微升）或吗啡与HU - 210联合注射到腹外侧PAG。重复注射吗啡导致第3天吗啡剂量 - 反应曲线向右移动（即产生了耐受性）。预先用吗啡与HU - 210联合处理的大鼠未出现明显耐受性。在仅用HU - 210预处理的大鼠中，吗啡的抗伤害感受作用增强。用大麻素受体拮抗剂AM - 251预处理大鼠可阻断这种增强作用，并且在一周后测试时这种增强作用也消失了。向PAG急性微量注射HU - 210可拮抗吗啡的抗伤害感受作用，这表明HU - 210诱导的吗啡抗伤害感受增强是一种代偿反应。正如所假设的，没有证据表明吗啡和HU - 210之间存在交叉耐受性。事实上，大麻素预处理增强了向腹外侧PAG微量注射吗啡的抗伤害感受作用。这些发现表明，交替使用阿片类药物和大麻素治疗可能在治疗上具有优势，可防止耐受性的产生并增强吗啡的抗伤害感受作用。
