KAPPA-ANTINOCICEPTIVE ACTIVITY OF SPIRADOLINE IN THE COLD-WATER TAIL-FLICK ASSAY IN RATS

Spiradoline (U62066E) a racemic mixture of the two enantiomers U63639( +) and U63640(-), appears to have kappa opioid receptor activity, but the contribution of each enantiomer toward this activity is still in q uestion. To determine the activity of each enantiomer in comparison to the racemic mixture, the three forms were tested in the cold-water ta il-nick (CWTF) assay in male Sprague-Dawley rats. Antinociception by s piradoline was completely antagonized by naloxone 0.50 mg/kg, a dose f ive times that required to antagonize antinociception by fentanyl in t his same assay. In a second series of tests, fentanyl induced antinoci ception was markedly reduced, while spiradoline-induced antinociceptio n was essentially unchanged, in methadone tolerant animals. Of the ena ntiomers, only U63640 produced antinociception, whereas U63639 failed to affect the nociceptive response. Additionally, spiradoline failed t o produce antinociception in animals pretreated with norbinaltorphimin e (kappa receptor specific), but antinociception was not affected in a nimals pretreated with beta-funaltrexamine (mu receptor specific). The se results show that spiradoline is a full antinociceptive agonist in the CWTF assay and that the effects of the drug are mediated through k appa opioid receptors. (C) 1998 Elsevier Science Inc.