Leonard Michael Z, Alapafuja Shakiru O, Ji Lipin, Shukla Vidyanand G, Liu Yingpeng, Nikas Spyros P, Makriyannis Alexandros, Bergman Jack, Kangas Brian D
Harvard Medical School, Department of Psychiatry, Boston, Massachusetts (J.B., B.D.K.); McLean Hospital, Preclinical Pharmacology Laboratory, Belmont, Massachusetts (M.Z.L., J.B., B.D.K.); MakScientific LLC, Burlington, Massachusetts (S.O.A.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (L.J., V.G.S., Y.L., S.P.N., A.M.).
Harvard Medical School, Department of Psychiatry, Boston, Massachusetts (J.B., B.D.K.); McLean Hospital, Preclinical Pharmacology Laboratory, Belmont, Massachusetts (M.Z.L., J.B., B.D.K.); MakScientific LLC, Burlington, Massachusetts (S.O.A.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (L.J., V.G.S., Y.L., S.P.N., A.M.)
J Pharmacol Exp Ther. 2017 Dec;363(3):314-323. doi: 10.1124/jpet.117.244392. Epub 2017 Sep 25.
An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type 1 (CB) receptor agonists such as Δ-tetrahydrocannabinol are increasingly used for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids -arachidonoylethanolamine [AEA (or anandamide)] and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB agonist-like subjective effects, as reflected in CB-related discriminative stimulus effects in laboratory subjects. Squirrel monkeys ( = 8) that discriminated the CB full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, the inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (JZL195, AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB-related discriminative stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were nonsurmountably antagonized by low doses of rimonabant. Additionally, FAAH or MGL inhibition revealed CB-like subjective effects produced by AEA but not by 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB receptor-mediated subjective effects.
对内源性大麻素系统的深入了解为疼痛及其他行为障碍的药物研发提供了新途径。外源性大麻素1型（CB）受体激动剂，如Δ-四氢大麻酚，因其药用作用而被越来越多地使用；然而，其效用因对与滥用相关的主观效应的担忧而受到限制。这使得人们越来越关注通过抑制分解代谢酶间接增强高度不稳定的内源性大麻素——花生四烯酸乙醇胺[AEA（或花生四烯酸乙醇胺）]和/或2-花生四烯酸甘油酯（2-AG）活性的临床益处。本研究旨在确定这些作用是否会导致CB激动剂样的主观效应，这在实验室受试者的CB相关辨别刺激效应中有所体现。将能够区分CB完全激动剂AM4054（0.01 mg/kg）与赋形剂的松鼠猴（n = 8）用于研究，首先研究脂肪酸酰胺水解酶（FAAH）或单酰甘油脂肪酶（MGL）单独或联合使用的抑制剂[FAAH（URB597，AM4303）；MGL（AM4301）；FAAH/MGL（JZL195，AM4302）]，其次研究内源性大麻素AEA和2-AG单独给药或酶抑制后产生CB激动剂样效应的能力。结果表明，CB相关辨别刺激效应是由FAAH和MGL的联合而非选择性抑制产生的，并且这些效应被低剂量的利莫那班不可逾越地拮抗。此外，FAAH或MGL抑制揭示了AEA产生的CB样主观效应，但2-AG未产生。综上所述，目前的数据表明，通过酶抑制联合而非选择性增强AEA或2-AG活性的治疗效果可能伴随着CB受体介导的主观效应。
