title: Inhibition of cholinergic transmission by opiates in ileal myenteric plexus is mediated by kappa receptor. Involvement of regulatory inhibitory G protein and calcium N-channels.
abstract: Opiates are known to influence intestinal motility via modulation of cholinergic transmission. The aims of this study are to characterize the opioid receptor subtype that modulates cholinergic transmission and to investigate the intracellular mechanism responsible for inhibition of acetylcholine (ACh) release by opiates using longitudinal muscle-myenteric plexus preparations of the guinea pig ileum. The kappa-receptor agonist U50488H and the mu-receptors agonist [D-Ala2,N-Me-Phe4, Gly5-ol]enkephalin, inhibited the release of ACh evoked by electrical stimulation (0.2 and 2 Hz) in a dose-dependent fashion, whereas the delta-receptor agonist DPDPE, had no effect. ACh release evoked by depolarization with veratridine, which was more analogous to high frequency stimulation, was inhibited only by U50488H. Pertussis toxin abolished the inhibitory effect of U50488H on veratridine-induced ACh release suggesting that the principal mechanism by which opiates inhibit cholinergic transmission is via activation of an inhibitory regulatory G protein. Veratridine-stimulated release of ACh was antagonized by omega-Conotoxin GVIA (a preferential N channel blocker) but was not affected by nifedipine (an L channel blocker) or nickel (a T channel blocker). U50488H did not produce further inhibition of veratridine-evoked ACh release in the presence of omega-Conotoxin GVIA. These results suggest that both kappa- and mu-agonists can modulate cholinergic transmission, although the kappa-agonist appears to be more potent. The kappa receptors modulate ACh release by inhibition of N-type voltage-sensitive Ca++ channels via a pertussis toxin-sensitive G protein in guinea pig ileum.
authors.affiliation: Department of Internal Medicine, University of Medical Center, Ann Arbor.
authors.forename: Y
authors.initials: Y
authors.lastname: Kojima
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: M
authors.initials: M
authors.lastname: Fujina
authors.forename: C
authors.initials: C
authors.lastname: Owyang
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects* / Q000378:metabolism; D009294:Narcotics / Q000494:pharmacology*; D037342:Pertussis Toxin; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D014701:Veratridine / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D004745:Enkephalins; D009294:Narcotics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D010566:Virulence Factors, Bordetella; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D014701:Veratridine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000109:Acetylcholine