PT  - JOURNAL ARTICLE
AU  - Joshi, S. K.
AU  - Gebhart, G. F.
TI  - Nonopioid Actions of U50,488 Enantiomers Contribute to Their Peripheral Cutaneous Antinociceptive Effects
AID  - 10.1124/jpet.103.049023
DP  - 2003 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 919--924
VI  - 305
IP  - 3
4099  - http://jpet.aspetjournals.org/content/305/3/919.short
4100  - http://jpet.aspetjournals.org/content/305/3/919.full
SO  - J Pharmacol Exp Ther2003 Jun 01; 305
AB  - The ability of arylacetamide κ-opioid receptor agonists (κ-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 κ-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 κ-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 κ-ORAs can contribute to their peripheral antinociceptive actions. The American Society for Pharmacology and Experimental Therapeutics