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 question. To determine the activity of each enantiomer in comparison to the racemic mixture, the three forms were tested in the cold-water tail-flick (CWTF) assay in male Sprague-Dawley rats. Antinociception by spiradoline was completely antagonized by naloxone 0.50 mg/kg, a dose five times that required to antagonize antinociception by fentanyl in this same assay. In a second series of tests, fentanyl-induced antinociception was markedly reduced, while spiradoline-induced antinociception was essentially unchanged. in methadone-tolerant animals. Of the enantiomers, only U63640 produced antinociception, whereas U63639 failed to affect the nociceptive response. Additionally, spiradoline failed to produce antinociception in animals pretreated with norbinaltorphimine (kappa receptor specific), but antinociception was not affected in animals pretreated with beta-funaltrexamine (mu receptor specific). These results show that spiradoline is a full antinociceptive agonist in the CWTF assay and that the effects of the drug are mediated through kappa opioid receptors.