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 δ-opioid receptors

Abstract

Male Swiss–Webster mice were injected intracerebroventricularly (i.c.v.) with [ d-Pen 2, d-Pen 5]enkephalin (DPDPE), a δ 1-opioid receptor agonist (20 μg 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 [ 3H]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 δ 2-opioid receptor agonist (20 μg 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 B max of [ 3H]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 [ 3H]DPDPE to bind to brain membranes. Thus, multiple injections of δ 1- or δ 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 δ 1- and δ 2-opioid receptor agonist, on chronic administration, result in the down-regulation of δ 1-opioid receptors labeled with [ 3H]DPDPE.