Hruba Lenka, McMahon Lance R
Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, United States.
Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, United States.
Eur J Pharmacol. 2014 Mar 15;727:35-42. doi: 10.1016/j.ejphar.2014.01.041. Epub 2014 Jan 30.
Synthetic cannabinoid abuse and case reports of adverse effects have raised concerns about the pharmacologic mechanisms underlying in vivo effects. Here, a synthetic cannabinoid identified in abused products (HU-210) was compared to the effects of Δ(9)-THC and two other synthetic cannabinoid agonists used extensively in pre-clinical studies (CP 55,940 and WIN 55,212-2). One group of monkeys discriminated ∆(9)-THC (0.1mg/kg i.v.); a separate group received chronic ∆(9)-THC (1mg/kg/12h s.c.) and discriminated rimonabant (1mg/kg i.v.). CP 55,940, HU-210, ∆(9)-THC, and WIN 55,212-2 produced ∆(9)-THC lever responding. HU-210 had a long duration (i.e., 1-2 days), whereas that of the other cannabinoids was 5h or less. Rimonabant (1mg/kg) produced surmountable antagonism; single dose-apparent affinity estimates determined in the presence of ∆(9)-THC, CP 55,940, and WIN 55,212-2 did not differ from each other. In contrast, rimonabant (1mg/kg) produced a smaller rightward shift in the HU-210 dose-effect function. In ∆(9)-THC treated monkeys, the relative potency of CP 55,940, ∆(9)-THC, and WIN 55,212-2 to attenuate the discriminative stimulus effects of rimonabant was the same as that evidenced in the ∆(9)-THC discrimination, whereas HU-210 was unexpectedly more potent in attenuating the effects of rimonabant. In conclusion, the same receptor subtype mediates the discriminative stimulus effects of ∆(9)-THC, CP 55,940 and WIN 55,212-2. The limited effectiveness of rimonabant to either prevent or reverse the effects of HU-210 appears to be due to very slow dissociation or pseudo-irreversible binding of HU-210 at cannabinoid receptors.
合成大麻素滥用及不良反应的病例报告引发了人们对其体内效应潜在药理机制的关注。在此，将在滥用产品中发现的一种合成大麻素（HU - 210）与Δ(9)-四氢大麻酚（Δ(9)-THC）以及另外两种在临床前研究中广泛使用的合成大麻素激动剂（CP 55,940和WIN 55,212 - 2）的效应进行了比较。一组猴子辨别Δ(9)-THC（0.1毫克/千克静脉注射）；另一组接受慢性Δ(9)-THC（1毫克/千克/12小时皮下注射）并辨别利莫那班（1毫克/千克静脉注射）。CP 55,940、HU - 210、Δ(9)-THC和WIN 55,212 - 2均产生了Δ(9)-THC杠杆反应。HU - 210的作用持续时间较长（即1 - 2天），而其他大麻素的作用持续时间为5小时或更短。利莫那班（1毫克/千克）产生了可克服的拮抗作用；在存在Δ(9)-THC、CP 55,940和WIN 55,212 - 2的情况下测定的单剂量表观亲和力估计值彼此无差异。相比之下，利莫那班（1毫克/千克）使HU - 210剂量 - 效应函数的右移较小。在接受Δ(9)-THC治疗的猴子中，CP 55,940、Δ(9)-THC和WIN 55,212 - 2减弱利莫那班辨别刺激效应的相对效力与在Δ(9)-THC辨别实验中所证明的相同，而HU - 210在减弱利莫那班的效应方面出人意料地更有效。总之，同一受体亚型介导了Δ(9)-THC、CP 55,940和WIN 55,212 - 2的辨别刺激效应。利莫那班预防或逆转HU - 210效应的效果有限，这似乎是由于HU - 210在大麻素受体处的解离非常缓慢或具有假不可逆结合。
