Peripheral kappa-opioid receptors mediate the antinociceptive effect of fedotozine (correction of fetodozine) on the duodenal pain reflex inrat.
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.
Diop
L
L
Institut de Recherche Jouveinal, Fresnes, France.
Rivière
P J
PJ
Pascaud
X
X
Junien
J L
JL
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects / Q000503:physiopathology*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D011437:Propylamines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects*
D000700:Analgesics; D001593:Benzyl Compounds; D011437:Propylamines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; C067749:fedotozine