Effect of fedotozine on the cardiovascular pain reflex induced by distension of the irritated colon in the anesthetized rat.
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.
Langlois
A
A
Institut de Recherche Jouveinal, Fresnes, France.
Diop
L
L
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; D000085:Acetates; D019342:Acetic Acid; D000595:Amino Acid Sequence; D000758:Anesthesia; D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D008297:Male; D008969:Molecular Sequence Data; D010146:Pain / Q000503:physiopathology*; D011437:Propylamines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology
D000085:Acetates; D001593:Benzyl Compounds; D011437:Propylamines; D011758:Pyrroles; D011759:Pyrrolidines; D013876:Thiophenes; C054718:PD 117302; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C067749:fedotozine; D019342:Acetic Acid