Nonopioid Actions of U50,488 Enantiomers Contribute to Their Peripheral Cutaneous Antinociceptive Effects

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Abstract
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.