Male Swiss-Webster mice were injected intracerebroventricularly (i.c.v.) with [D-Pen2,D-Pen5]enkephalin (DPDPE), a delta 1-opioid receptor agonist (20 micrograms per mouse) twice a day for either 2 or 4 days. Vehicle injected mice served as controls. Treatment of mice with DPDPE for 2 or 4 days decreased its analgesic response by 44 and 76%, respectively in comparison to vehicle injected mice. Treatment of mice with DPDPE for 2 or 4 days decreased density (Bmax) of [3H]DPDPE to bind to brain homogenates by 77 and 76%, respectively, in comparison to vehicle injected controls but the apparent dissociation constant (kd) values were not altered. The effects of i.c.v. injections of [D-Ala2,Glu4]deltorphin II (deltorphin II), a delta 2-opioid receptor agonist (20 micrograms per mouse) twice a day for either 2 or 4 days on its analgesic response as well as on brain receptors for [3H]DPDPE were also determined. The analgesic response to deltorphin II decreased by 51 and 78%, respectively in mice treated with deltorphin II for 2 or 4 days, respectively. Two or four days treatment with deltorphin II decreased the Bmax of [3H]DPDPE by 76 and 87%, respectively. The 2-day treatment also increased the Kd value by 58%, but the 4-day treatment with deltorphin II had no effect on the Kd of [3H]DPDPE to bind to brain membranes. Thus, multiple injections of delta 1- or delta 2-opioid receptor agonists results in the development of tolerance to their analgesic action and the intensity of tolerance increases with the duration of treatment. Both delta 1- and delta 2-opioid receptor agonist, on chronic administration, result in the down-regulation of delta 1-opioid receptors labeled with [3H]DPDPE.