PERIPHERAL KAPPA-OPIOID RECEPTORS MEDIATE THE ANTINOCICEPTIVE EFFECT OF FETODOZINE ON THE DUODENAL PAIN REFLEX IN RAT

Fedotozine has been shown to act on gastrointestinal sensitivity throu gh peripheral kappa-opioid receptors. The present study investigated t he action of fedotozine and reference compounds, morphine and (+/-)-U- 50,488H, on duodenal pain in anesthetized rats. The noxious stimulus w as 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 (ED(50) = 1.87 mg/kg) but had n o effect at doses up to 300 mu g/rat by either intracerebroventricular (i.c.v.) or intrathecal routes (i.t.). The mu-opioid receptor agonist , morphine, was active by both i.v. (ED(50) = 0.62 mg/kg) and i.c.v. r outes (ED(50) = 2.17 mu g/rat) as was the kappa-opioid receptor agonis t, (+/-)-U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[ 1-pyrroli dinyy]cyclohexyl)b enzeneacetamide) (ED(50) = 0.25 mg/kg and 149 mu g/ rat for i.v. and i.c.v. routes, respectively). The selective kappa-opi oid receptor antagonist, nor-binaltorphimine (10 mg/kg s.c.), abolishe d 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, naloxon e (30 mu g/kg i.v.) blocked the response to morphine (1 mg/kg i.v.) bu t 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.