Solinas Marcello, Panlilio Leigh V, Tanda Gianluigi, Makriyannis Alexandros, Matthews Stephanie A, Goldberg Steven R
Preclinical Pharmacology Section, Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA.
Neuropsychopharmacology. 2005 Nov;30(11):2046-57. doi: 10.1038/sj.npp.1300754.
Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin. In rats intravenously self-administering heroin, we investigated effects of cannabinoid CB1 receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide. The natural cannnabinoid CB1 receptor agonist delta-9-tetrahydrocannabinol (THC, 0.3-3 mg/kg i.p.) did not alter self-administration of heroin under a fixed-ratio one (FR1) schedule, except at a high 3 mg/kg dose which decreased heroin self-administration. Under a progressive-ratio schedule, however, THC dose-dependently increased the number of 50 mug/kg heroin injections self-administered per session and the maximal ratio completed (break-point), with peak increases at 1 mg/kg THC. In addition, 1 mg/kg THC increased break-points and injections self-administered over a wide range of heroin injection doses (25-100 microg/kg), indicating an increase in heroin's reinforcing efficacy and not its potency. The synthetic cannabinoid CB1 receptor agonist WIN55,212-2 (0.3-3 mg/kg i.p.) had effects similar to THC under the progressive-ratio schedule. In contrast, AM-404 (1-10 mg/kg i.p.), an inhibitor of transport of anandamide, and URB-597 (0.01-0.3 mg/kg i.p.), an inhibitor of the enzyme fatty acid amide hydrolase (FAAH) that degrades anandamide, or their combination, did not increase reinforcing efficacy of heroin at any dose tested. Thus, activation of cannabinoid CB1 receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid CB1 receptors and mu-opioid receptors and their signaling pathways, rather than by an opioid-induced release of endogenous cannabinoids.
越来越多的证据表明，内源性大麻素系统参与了海洛因的强化作用。在静脉注射海洛因的大鼠中，我们研究了大麻素CB1受体激动剂以及阻断内源性大麻素花生四烯乙醇胺转运或代谢的化合物的作用。天然大麻素CB1受体激动剂Δ⁹-四氢大麻酚（THC，0.3 - 3毫克/千克，腹腔注射）在固定比率为1（FR1）的给药方案下，除了高剂量3毫克/千克时会减少海洛因的自我给药外，并不会改变海洛因的自我给药情况。然而，在累进比率给药方案下，THC剂量依赖性地增加了每次实验中自我注射50微克/千克海洛因的次数以及完成的最大比率（断点），在THC剂量为1毫克/千克时达到峰值增加。此外，1毫克/千克的THC在广泛的海洛因注射剂量（25 - 100微克/千克）范围内增加了断点和自我注射次数，这表明海洛因的强化效力增加而非其效能增加。合成大麻素CB1受体激动剂WIN55,212 - 2（0.3 - 3毫克/千克，腹腔注射）在累进比率给药方案下具有与THC相似的作用。相比之下，花生四烯乙醇胺转运抑制剂AM - 404（1 - 10毫克/千克，腹腔注射）和降解花生四烯乙醇胺的脂肪酸酰胺水解酶（FAAH）抑制剂URB - 597（0.01 - 0.3毫克/千克，腹腔注射），或它们的组合，在任何测试剂量下都不会增加海洛因的强化效力。因此，大麻素CB1受体的激活促进了海洛因的强化效力，这似乎是由大麻素CB1受体与μ-阿片受体及其信号通路之间的相互作用介导的，而不是由阿片类药物诱导的内源性大麻素释放介导的。
