title: Nonopioid actions of U50,488 enantiomers contribute to their peripheral cutaneous antinociceptive effects.
abstract: The ability of arylacetamide kappa-opioid receptor agonists (kappa-ORAs) to block sodium channels by a nonopioid mechanism has been previously documented. The present experiments were undertaken to test whether two enantiomers of the arylacetamide kappa-ORA (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488), (+)-(1R,2R)-U50,488 and (-)-(1S,2S)-U50,488, are antinociceptive in the formalin model by a peripheral, nonopioid receptor-mediated mechanism. Although both enantiomers have been previously shown to block sodium channels with comparable potencies, only (-)-(1S,2S)-U50,488 has activity at the kappa-opioid receptor (KOR). In the formalin test, intrapaw administration of U50,488 enantiomers as well as lidocaine exhibited significant dose-related attenuation of formalin-induced flinching behavior. The rank order of potency of the drugs tested was (-)-(1S,2S)-U50,488 > (+)-(1R,2R)-U50,488 > lidocaine. The antinociception produced by lower doses of (-)-(1S,2S)-U50,488 was blocked by intrapaw nor-binaltorphimine as well as by antisense knockdown of the KOR. Such pretreatments, however, did not block the antinociception produced by (+)-(1R,2R) U50,488, lidocaine, or higher doses of (-)-(1S,2S)-U50,488. These data suggest that the sodium channel blocking effects of U50,488 and similar kappa-ORAs can contribute to their peripheral antinociceptive actions.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA. shailen-joshi@uiowa.edu
authors.forename: S K
authors.initials: SK
authors.lastname: Joshi
authors.forename: G F
authors.initials: GF
authors.lastname: Gebhart
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000737:chemistry / Q000494:pharmacology*; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D008968:Molecular Conformation; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000700:Analgesics; D000779:Anesthetics, Local; D017473:Receptors, Opioid, kappa; D026941:Sodium Channel Blockers; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D008012:Lidocaine