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Kappa Antinociceptive Activity of Spiradoline in the Cold-Water Tail-Flick Assay in Rats

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Abstract

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.

Section snippets

Subjects

Male Sprague–Dawley rats, weighing 300 to 500 g, were approved for use in the following experiments by the All-University Committee on Animal Use and Care of Michigan State University. All rats were trained over a 2-month period to lie quietly in a towel that was snugly secured around them. Training started for rats between the ages of 60 to 80 days. After approximately 6 weeks of training, rats accommodated to being restrained in the towels without struggling. The subjects were reinforced

Dose–Response Patterns of the Agonists in CWTF

Results of log dose–response analyses in the CWTF demonstrated that spiradoline acted as a full agonist in producing antinociception with an AD50 of 0.56 mg/kg SC (Fig. 1B). This result is in good agreement with those of spiradoline tested in other nociceptive assays in the rat (26). However, the dose–response analysis of spiradoline was somewhat limited in that higher doses also produced behaviors that tended to confound observations. For reporting of accurate observations, subjects had to

Discussion

The dose–response curves of fentanyl and spiradoline described above indicate that mu and kappa agonists can be equally efficacious as antinociceptives in the CWTF at −10°C. Spiradoline appears to act as a full agonist in the CWTF at −10°C and appears to produce its antinociceptive effect by selective action at kappa receptors. It is important to note that this study used a 60-s latency cutoff, which has been shown to separate strong narcotic analgesics from mixed agonist-antagonist drugs (21).

Acknowledgements

The authors wish to thank Ms. Stephanie Gollakner for her excellent skills and experience in animal handling and training and for her assistance in carrying out these experiments.

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