Mulè Flavia, Amato Antonella, Baldassano Sara, Serio Rosa
Dipartimento di Biologia cellulare e dello Sviluppo, Viale delle Scienze, Università di Palermo, 90128 Palermo, Italy.
Pharmacol Res. 2007 Sep;56(3):185-92. doi: 10.1016/j.phrs.2007.06.002. Epub 2007 Jun 21.
While most of the studies concerning the role of cannabinoids on gastric motility have focused the attention on the gastric emptying in in vivo animal models, there is little information about the cannabinoid peripheral influence in the stomach. In addition, the functional features of CB2 receptors in the gastrointestinal tract have been poorly characterized. The purpose of the present study was to investigate the effects of cannabinoid drugs on the excitatory cholinergic and inhibitory non-adrenergic non-cholinergic (NANC) neurotransmission in mouse isolated gastric preparations. Intraluminal pressure from isolated whole stomach was recorded and mechanical responses induced by electrical field stimulation (EFS) were analyzed in different experimental conditions. EFS (0.5ms duration, supramaximal voltage, in trains of 5s, 2-16Hz) caused a cholinergic contraction, which was abolished by atropine or tetrodotoxin (TTX). The cannabinoid receptor agonist, WIN 55,212-2, the endogenous ligand, anandamide, the selective CB1 receptor agonist ACEA, and the selective CB2 receptor agonists, JWH015 and JWH133, produced a concentration-dependent reduction of the EFS-evoked cholinergic contractions. SR141716A, CB1 receptor antagonist, significantly attenuated the inhibitory effects induced by WIN 55,212-2, anandamide or ACEA, without affecting those caused by JWH133. AM630, CB2 receptor antagonist, reduced the inhibitory effects induced by WIN 55,212-2, anandamide, JWH015 or JWH133, without affecting those caused by ACEA. The joint application of SR141716A and AM630 was able of fully preventing the WIN 55,212-2 and anandamide actions. The cannabinoid antagonists failed per se to affect the neurally evoked responses. Cannabinoids did not modify the contractions produced by exogenous carbachol. In the presence of atropine and guanethidine (NANC conditions) EFS-induced TTX-sensitive relaxation consisting in an early and rapid component followed by a second slow phase, which were unaffected by cannabinoid drugs. In conclusion, the present results suggest that cannabinoids play a prejunctional modulatory role on the cholinergic excitatory transmission without affecting the NANC inhibitory transmission. In addition, this study provides experimental evidence that also the activation of CB2 receptors is able to reduce cholinergic neurotransmission in the mouse stomach.
虽然大多数关于大麻素对胃动力作用的研究都集中在体内动物模型的胃排空上，但关于大麻素在胃中的外周影响的信息却很少。此外，胃肠道中CB2受体的功能特性尚未得到充分表征。本研究的目的是研究大麻素药物对小鼠离体胃制备物中兴奋性胆碱能和抑制性非肾上腺素能非胆碱能（NANC）神经传递的影响。记录离体全胃的腔内压力，并在不同实验条件下分析电场刺激（EFS）诱导的机械反应。EFS（持续时间0.5毫秒，超最大电压，以5秒为一组，频率2-16赫兹）引起胆碱能收缩，该收缩可被阿托品或河豚毒素（TTX）消除。大麻素受体激动剂WIN 55,212-2、内源性配体花生四烯乙醇胺、选择性CB1受体激动剂ACEA以及选择性CB2受体激动剂JWH015和JWH133均产生浓度依赖性地降低EFS诱发的胆碱能收缩作用。CB1受体拮抗剂SR141716A显著减弱了WIN 55,212-2、花生四烯乙醇胺或ACEA诱导的抑制作用，但不影响JWH133引起的抑制作用。CB2受体拮抗剂AM630降低了WIN 55,212-2、花生四烯乙醇胺、JWH015或JWH133诱导的抑制作用，但不影响ACEA引起的抑制作用。联合应用SR141716A和AM630能够完全阻断WIN 55,212-2和花生四烯乙醇胺的作用。大麻素拮抗剂本身不会影响神经诱发的反应。大麻素不会改变外源性卡巴胆碱产生的收缩。在阿托品和胍乙啶存在的情况下（NANC条件），EFS诱导的TTX敏感的舒张包括一个早期快速成分和随后的第二个缓慢阶段，大麻素药物对其没有影响。总之，目前的结果表明，大麻素在胆碱能兴奋性传递中起突触前调节作用，而不影响NANC抑制性传递。此外，本研究提供了实验证据，表明激活CB2受体也能够减少小鼠胃中的胆碱能神经传递。
