Involvement of kappa-opioid receptors in opioid dependence/withdrawal: studies using butorphanol

The dependence liability of a class of opioid agonist/antagonist analgesics, e.g. pentazocine, butorphanol, and buprenorphine, is widely recognized. However, the relative involvement of mu-, delta-, and kappa-opioid receptors mediating physical dependence on these compounds is not completely known. In the present study, butorphanol dependence was produced by continuous intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/h) for 3 days in male Sprague-Dawley rats. Nor-binaltorphimine, a long-acting kappa-opioid receptor antagonist, and naloxone, a nonspecific antagonist, were administered i.c.v. to precipitate withdrawal in butorphanol-dependent animals, so as to investigate the involvement of central kappa-opioid receptors in opioid dependence. ED50 ratios (naloxone/nor-binaltorphimine) for eliciting withdrawal signs were: teeth-chattering (1.25), yawning (2.13), and ejaculation (0.72). Our data indicate that nor-binaltorphimine precipitated withdrawal behaviors similar to those precipitated by naloxone. It appears that central kappa-opioid receptors may play a major role in the development of butorphanol dependence in rats.