Effects of multiple intracerebroventricular injections of [D-Pen(2),D-Pen(5)]enkephalin and [D-Ala(2),Glu(4)]deltorphin II on tolerance to their analgesic action and on brain delta-opioid receptors

Male Swiss-Webster mice were injected intracerebroventricularly (i.c.v.) with [D-Pen(2),D-Pen(5)]enkephalin (DPDPE), a delta(1)-opioid receptor agonist (20 mu g 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 the receptor density (B-max) of [H-3]DPDPE to bind to brain homogenates by 77 and 76%, respectively, in comparison to vehicle injected controls but the apparent dissociation constant (K-d) values were not altered. The effects of i.c.v. injections of [D-Ala(2),Glu(4)]deltorphin II (deltorphin II), a delta(2)-opioid receptor agonist (20 mu g per mouse) twice a day for either 2 or 4 days on its analgesic response as well as on brain receptors for [H-3]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 B-max of [H-3]DPDPE by 76 and 87%, respectively. The 2-day treatment also increased the K-d value by 58%, but the 4-day treatment with deltorphin II had no effect on the K-d of [H-3]DPDPE to bind to brain membranes. Thus, multiple injections of delta(1)- or delta(2)-opioid receptor agonists result 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 [H-3]DPDPE.