In experiments to evaluate responses to the activation of cerebral delta-opioid receptors, repeated daily injection of the selective delta-opioid agonist Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 ([D-Ala2]deltorphin II) into rat brain resulted in the development of tolerance, whereas repeated daily injection or continuous infusion of morphine resulted in sensitization to the behavioral activating effects of the delta-opioid agonist. Although the rats did not modify their spontaneous locomotor activity after morphine withdrawal, they became markedly hyperresponsive to the locomotor and stereotypy-producing effects of a challenge dose of the delta-opioid agonist. Sensitization to activation of delta-opioid receptors persisted for at least 60 days after discontinuing morphine treatment. These results show that the development of tolerance and long-term sensitization to opioids involves delta-opioid as well as mu-opioid receptors.