Opioids are the most effective drugs known for the relief of pain; however, their clinical utility is limited by a number of undesirable effects such as the production of tolerance, physical dependence and a tendency to be abused. A considerable amount of research has been devoted to developing opioid analgesics with low physical dependence and abuse liabilities. In this regard, the partial agonists and the agonist-antagonists have shown some utility as analegics; however, the dysphoric effects of some of these drugs has limited their use.
The aim of the experiments proposed here is to examine the behavioral pharmacology of selected partial agonists and mixed agonist-antagonists as analgesics. This will be done by examining a number of drugs under a shock titration procedure in squirrel monkeys and making comparisons between compounds in terms of the shape of their dose-effect curves, the ease with which they are antagonized and the occurrence of cross tolerance among them. Compounds selected for examination include the partial agonists buprenorphine and picenadol, the putative kappa agonists bremazocine, nalbuphine and U-50, 488 and the separate isomers of the sigma agonist n-allyl normetazocine. These compounds will be examined alone and in the presence of various opioid antagonists thought be have varying activity at mu, kappa or delta receptors. In addition, the nonopioid analgesic clonidine will be examined. Finally, the type of stimulus used to assess analgesia will be examined as a determinant of drug effect.
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