Hasanein Parisa
Department of Biology, School of Basic Sciences, Bu-Ali Sina University, Hamadan, Iran.
Neurosci Lett. 2009 Oct 25;462(3):230-4. doi: 10.1016/j.neulet.2009.07.026. Epub 2009 Jul 16.
Cholestasis is associated with increased activity of the endogenous opioid system that results in analgesia. Endocannabinoid system can reduce pain sensitivity. Considering the interaction that has been shown between the endogenous opioid and endocannabinoid systems in nociception processing, we studied the effect of AM404, an endocannabinoid transport inhibitor, on modulation of nociception in cholestasis, a model of elevated endogenous opioid tone. Cholestasis was induced by ligation of the main bile duct using two ligatures and transection of the duct at the midpoint between them. A significant increase (P<0.01) in TF was observed in cholestatic rats compared to unoperated and sham rats. AM404 (10 mg/kg, i.p.) significantly increased TFL at 5, 30 min but not 60 min after injection in cholestatic animals compared to the vehicle treated cholestatic group (P<0.05, P<0.001, respectively). AM404 injection to unoperated and sham rats did not alter baseline TFL. The effect of AM404 in cholestatic rats was blocked by co-administration of a CB(1) receptor antagonist, AM251 (1 mg/kg, i.p.) but not by the CB2 receptor antagonist, SR144528 (1 mg/kg, i.p.). Naloxone injection blocked the antinociception induced by cholestasis in bile duct ligated group. Antinociception produced by injection of AM404 in cholestatics was also attenuated by co-administration of naloxone. These data show that AM404 potentiates antinociception induced by cholestasis and indicate that there are possible interactions between opioid and cannabinoid systems in this experimental model of elevated endogenous opioid tone. The inhibitory effects of AM404 in this model are mediated by cannabinoid CB(1) and not CB(2) receptors.
胆汁淤积与导致镇痛的内源性阿片系统活性增加有关。内源性大麻素系统可降低疼痛敏感性。鉴于已显示内源性阿片和内源性大麻素系统在痛觉处理过程中存在相互作用，我们研究了内源性大麻素转运抑制剂AM404对胆汁淤积（一种内源性阿片张力升高的模型）中痛觉调制的影响。通过使用两道结扎线结扎胆总管并在两道结扎线之间的中点横断胆管来诱导胆汁淤积。与未手术和假手术大鼠相比，胆汁淤积大鼠的TF显著增加（P<0.01）。与溶剂处理的胆汁淤积组相比，在胆汁淤积动物中，注射AM404（10mg/kg，腹腔注射）在注射后5分钟、30分钟时显著增加TFL，但在60分钟时未增加（分别为P<0.05，P<0.001）。向未手术和假手术大鼠注射AM404并未改变基线TFL。在胆汁淤积大鼠中，AM404的作用被共同给予CB(1)受体拮抗剂AM251（1mg/kg，腹腔注射）所阻断，但未被CB2受体拮抗剂SR144528（1mg/kg，腹腔注射）所阻断。注射纳洛酮可阻断胆管结扎组中胆汁淤积诱导的抗伤害感受。共同给予纳洛酮也减弱了在胆汁淤积动物中注射AM404所产生的抗伤害感受。这些数据表明，AM404增强了胆汁淤积诱导的抗伤害感受，并表明在这个内源性阿片张力升高的实验模型中，阿片和大麻素系统之间可能存在相互作用。在这个模型中，AM404的抑制作用是由大麻素CB(1)而非CB(2)受体介导的。
