When administered repeatedly, in conjunction with hot plate testing, naloxone and naltrexone have the paradoxical effect of producing antinociception in rats and mice. Recently, we have found that the sub-acute selective blockade of mu opioid receptors leads to the development of antinociception and an augmentation of kappa receptor-mediated antinociception. In this study, acute delta/kappa antagonist treatment produced a significant decrease in paw lick latency in rats displaying antinociception induced by sub-acute mu blockade, however, the response level of these animals was still significantly above the baseline. In addition, rats receiving sub-acute combined mu and delta antagonist treatment took longer to develop an antinociceptive response than those treated with a mu antagonist alone. Sub-acute selective blockade of kappa or delta opioid receptors had no overall effect on paw lick latency during the course of 5 days of hot plate testing. The results indicate that delta receptor activity may play a role in the antinociception induced by sub-acute mu blockade. However, while delta antagonist treatment effected the expression, it did not completely attenuate the antinociception induced by sub-acute mu blockade suggesting that there is still a significant non-opioid component to this analgesic response. The results of a final experiment, in which acute delta antagonist treatment had no effect on antinociception induced by repeated systemic injections of naloxone, supported this hypothesis.