Butorphanol, a synthetic agonist/antagonist, has been shown to act on mu-, delta- and kappa-opioid receptors. However, the relative involvement of opioid receptor subtypes in mediating butorphanol dependence is not known. In the present study, naltrindole, a delta-selective non-peptide antagonist, was administered intracerebroventricularly (i.c.v.) to mask supraspinal delta-opioid receptors before and during the induction of butorphanol dependence. Treatment with naltrindole (0.1, 1, or 10 nmol/5 microliters per rat) significantly blocked naloxone-, a nonspecific antagonist, precipitated butorphanol withdrawal behaviors (escape behavior, teeth-chattering, wet shakes, forepaw tremors, ptosis, diarrhea, body weight loss, and hypothermia) at all doses tested, and decreased ejaculation at 0.1 nmol in butorphanol-infused rats. In contrast, naltrindole treatment had no effect on yawning, nor urination. These results indicate that central delta-opioid receptors are involved in mediating butorphanol dependence in rats.