Langlois A, Diop L, Rivière P J, Pascaud X, Junien J L
Institut de Recherche Jouveinal, Fresnes, France.
Eur J Pharmacol. 1994 Dec 27;271(2-3):245-51. doi: 10.1016/0014-2999(94)90780-3.
The effect of fedotozine was evaluated in a model of colonic hypersensibility to balloon distension in anesthetized rats. Acetic acid (0.6%, intracolonically) significantly enhanced the hypotension reflex response to colonic distension (P < 0.05). At a noxious pain pressure (75 mm Hg), fedotozine ((+)-(-1R)-1-phenyl-1-[(3,4,5- trimethoxy)benzyloxymethyl]-N,N-dimethyl-n-propylamine) had no effect at 0.6 and 1 mg/kg i.v. in saline-treated rats and higher doses were required to produce antinociception (ED50 = 2.57 mg/kg i.v.). By contrast, fedotozine at 0.6 and 1 mg/kg i.v. displayed 38 and 54% antinociception (P < 0.05) respectively, in acetic acid-treated animals, leading to a decrease in its ED50 (1.15 mg/kg i.v.). Similar results were obtained with (+/-)-trans-N-methyl-N-[2-(pyrrolidinyl)-cyclohexyl]benzo[b]-thiophene- 4-acetamide (PD-117,302), a kappa-opioid receptor agonist, while the antinociceptive action of morphine and a kappa-opioid receptor agonist, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl)benzenacetamide ((+/-)-U-50,488H), was identical in control and acetic acid-treated animals. Nor-binaltorphimine, a selective kappa-opioid receptor antagonist, reversed the enhanced antinociceptive activity of fedotozine and PD-117,302. It is concluded that acetic acid induces colonic hypersensibility to painful mechanical stimuli and that some but not all kappa-opioid receptor ligands can have enhanced efficacy in this pathological situation.
在麻醉大鼠结肠对球囊扩张的超敏反应模型中评估了非多托嗪的作用。乙酸（0.6%，结肠内注射）显著增强了对结肠扩张的低血压反射反应（P<0.05）。在有害疼痛压力（75毫米汞柱）下，非多托嗪（(+)-(-1R)-1-苯基-1-[(3,4,5-三甲氧基)苄氧基甲基]-N,N-二甲基-n-丙胺）在生理盐水处理的大鼠中静脉注射0.6和1毫克/千克时无效，需要更高剂量才能产生镇痛作用（半数有效量=2.57毫克/千克静脉注射）。相比之下，在乙酸处理的动物中，静脉注射0.6和1毫克/千克的非多托嗪分别显示出38%和54%的镇痛作用（P<0.05），导致其半数有效量降低（1.15毫克/千克静脉注射）。κ-阿片受体激动剂(+/-)-反式-N-甲基-N-[2-(吡咯烷基)-环己基]苯并[b]噻吩-4-乙酰胺（PD-117,302）也得到了类似结果，而吗啡和κ-阿片受体激动剂反式-(+/-)-3,4-二氯-N-甲基-N-(2-[1-吡咯烷基]环己基)苯乙酰胺（(+/-)-U-50,488H）在对照动物和乙酸处理动物中的镇痛作用相同。选择性κ-阿片受体拮抗剂诺美沙朵逆转了非多托嗪和PD-117,302增强的镇痛活性。结论是，乙酸诱导结肠对疼痛性机械刺激的超敏反应，并且一些但不是所有的κ-阿片受体配体在这种病理情况下可以具有增强的效力。
