Diop L, Rivière P J, Pascaud X, Junien J L
Institut de Recherche Jouveinal, Fresnes, France.
Eur J Pharmacol. 1994 Dec 12;271(1):65-71. doi: 10.1016/0014-2999(94)90265-8.
Fedotozine has been shown to act on gastrointestinal sensitivity through peripheral kappa-opioid receptors. The present study investigated the action of fedotozine and reference compounds, morphine and (+/-)-U-50,488H, on duodenal pain in anesthetized rats. The noxious stimulus was produced by duodenal distension (100 mm Hg; 30 s). Fedotozine (1-5 mg/kg i.v.) produced a dose-dependent inhibition of the cardiovascular reflex induced by duodenal distension (ED50 = 1.87 mg/kg) but had no effect at doses up to 300 micrograms/rat by either intracerebroventricular (i.c.v.) or intrathecal routes (i.t.). The mu-opioid receptor agonist, morphine, was active by both i.v. (ED50 = 0.62 mg/kg) and i.c.v. routes (ED50 = 2.17 micrograms/rat) as was the kappa-opioid receptor agonist, (+/-)-U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl)benzeneacetamide) (ED50 = 0.25 mg/kg and 149 micrograms/rat for i.v. and i.c.v. routes, respectively). The selective kappa-opioid receptor antagonist, nor-binaltorphimine (10 mg/kg s.c.), abolished the response to fedotozine (5 mg/kg i.v.) and (+/-)-U-50,488H (2 mg/kg i.v.) but not that to morphine (1 mg/kg i.v.). In contrast, naloxone (30 micrograms/kg i.v.) blocked the response to morphine (1 mg/kg i.v.) but not that to fedotozine (5 mg/kg i.v.) or (+/-)-U-50,488H (2 mg/kg i.v.). It is concluded that the antinociceptive effects of fedotozine on duodenal pain are mediated by peripheral kappa-opioid receptors.
非多托嗪已被证明可通过外周κ-阿片受体作用于胃肠道敏感性。本研究调查了非多托嗪以及参比化合物吗啡和（±）-U-50,488H对麻醉大鼠十二指肠疼痛的作用。有害刺激由十二指肠扩张（100毫米汞柱；30秒）产生。非多托嗪（1 - 5毫克/千克静脉注射）对十二指肠扩张诱导的心血管反射产生剂量依赖性抑制（半数有效量=1.87毫克/千克），但通过脑室内（i.c.v.）或鞘内途径（i.t.）给予高达300微克/只大鼠的剂量时无效。μ-阿片受体激动剂吗啡通过静脉注射（半数有效量=0.62毫克/千克）和脑室内途径（半数有效量=2.17微克/只大鼠）均有活性，κ-阿片受体激动剂（±）-U-50,488H（反式-（±）-3,4-二氯-N-甲基-N-（2-[1-吡咯烷基]环己基）苯乙酰胺）也是如此（静脉注射和脑室内途径的半数有效量分别为0.25毫克/千克和149微克/只大鼠）。选择性κ-阿片受体拮抗剂诺-纳洛酮（10毫克/千克皮下注射）消除了对非多托嗪（5毫克/千克静脉注射）和（±）-U-50,488H（2毫克/千克静脉注射）的反应，但未消除对吗啡（1毫克/千克静脉注射）的反应。相反，纳洛酮（30微克/千克静脉注射）阻断了对吗啡（1毫克/千克静脉注射）的反应，但未阻断对非多托嗪（5毫克/千克静脉注射）或（±）-U-50,488H（2毫克/千克静脉注射）的反应。得出的结论是，非多托嗪对十二指肠疼痛的镇痛作用是由外周κ-阿片受体介导的。
