Sodium channel blocking actions of the kappa-opioid receptor agonist U50,488 contribute to its visceral antinociceptive effects.
The goal of the present study was to determine whether the kappa-opioid receptor agonist (ORA) U50,488 attenuates behavioral and primary afferent nerve responses to noxious colorectal distension (CRD) by sodium channel blockade. We tested the analgesic kappa-ORA (+/-)-trans U50,488, its enantiomers (-)-trans (1S,2S)-U50,488 and non kappa-ORA (+)-trans (1R,2R)-U50,488, and/or its diastereomer (-)-cis (1S,2R)-U50,488 for their ability to attenuate visceromotor and pelvic nerve afferent fiber responses to noxious CRD in vivo and voltage-activated sodium current in colon sensory neurons in vitro. In unanesthetized rats, subcutaneous administration of U50,488, (1S,2S)-U50,488, and (1R,2R)-U50,488 attenuated the behavioral visceromotor response to noxious CRD; the rank order of potency was: (1S,2S)-U50,488 > U50,488 angle quotation mark, right (1R,2R)-U50,488. U50,488 and its stereoisomers also inhibited responses of decentralized pelvic nerve afferent fibers to noxious CRD in a dose-dependent manner. Cumulative doses of 16 mg/kg of (1S,2S)-U50,488, (1S,2R)-U50,488, and (1R,2R)-U50,488 reduced responses to a mean 29, 30, and 47% of control, respectively. The mean inhibitory doses of these drugs were not different (range: 6.6-10.8 mg/kg). Sodium channel blockers mexiletine and carbamazepine mimicked the effect of U50,488. In contrast, the kappa-ORAs dynorphin (1-13) and ICI 204,488 were ineffective in attenuating pelvic nerve activity. Perfusion of (1S,2S)-U50,488, (1S,2R)-U50,488, or (1R,2R)-U50,488 on colon sensory neurons in vitro decreased voltage-activated sodium currents. This inhibition by U50,488 and its stereoisomers was not opioid receptor-mediated because it could not be reversed by the opioid receptor antagonist naloxone and was also not a G protein-mediated effect. The results reported here suggest that the visceral antinociceptive effects of U50,488 and its stereoisomers are contributed to by their peripheral sodium channel blocking actions.
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Department of Pharmacology, College of Medicine, The University of Iowa, Bowen Science Building, Iowa City, IA 52242, USA.
Joshi
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Kardos
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Gebhart
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D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000737:chemistry / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000737:chemistry / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology; D004399:Dynorphins / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008801:Mexiletine / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects*; D010388:Pelvis / Q000294:innervation; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D026941:Sodium Channel Blockers; D013237:Stereoisomerism
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000889:Anti-Arrhythmia Agents; D010446:Peptide Fragments; D017473:Receptors, Opioid, kappa; D026941:Sodium Channel Blockers; D008801:Mexiletine; D002220:Carbamazepine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C026843:dynorphin (1-13); D004399:Dynorphins