title: Pre- and post-synaptic effects of spiradoline and U-50488H, selective kappa opioid receptor agonists, in isolated ileum.
abstract: In guinea pig ileum, spiradoline (2 x 10(-6) M or greater) and U-50488H (3 x 10(-6) M or greater) suppressed contractile responses to acetylcholine (ACh), histamine, and BaCl2. Inhibition by spiradoline (2 x 10(-5) M) of ACh-induced contractions was not antagonized by pretreatment with naloxone (3 x 10(-4) M). Spiradoline (2 x 10(-8) M or greater) and U-50488H (3 x 10(-8) M or greater) caused dose-dependent inhibition of the contractile response of guinea pig ileum to transmural electric stimulation. The inhibitory effect of spiradoline or of U-50488H at low concentrations was reduced by a high concentration of naloxone (3 x 10(-4) M). Spiradoline at low concentrations ranging from 2 x 10(-9) to 2 x 10(-7) M reduced spontaneous contractions in rabbit ileum. Naloxone (3 x 10(-4) g/ml) antagonized the spiradoline-induced inhibition, but marked inhibition by spiradoline at 10(-4) g/ml was not restored by naloxone. These results suggest that both kappa agonists exert presynaptic inhibitory action on cholinergic nerve endings in the myenteric plexus at a low concentration range of 10(-9) to 10(-7) M and directly inhibit the smooth-muscle motility of the gut at greater concentrations.
authors.affiliation: Dept. of Pharmacology, Upjohn Pharmaceuticals Limited, Tsukuba Research Laboratories, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nomura
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000294:innervation*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009197:Myenteric Plexus / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D011817:Rabbits; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa
chemical_list: D000700:Analgesics; D011759:Pyrrolidines; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; C051272:spiradoline