title: Chronic effect of [D-Pen2,D-Pen5]enkephalin on rat brain opioid receptors.
abstract: In previous studies, we have demonstrated that chronic etorphine or [D-Ala2,D-Leu5]enkephalin (DADLE) treatment of rats results in the reduction of mu- and delta-opioid receptor binding activities as tolerance develops. As both etorphine and DADLE are relatively non-specific opioid ligands, interacting with both mu- and delta-receptors, these studies could not determine whether down-regulation of a specific receptor type occurs. Therefore, in the present studies, animals were rendered tolerant to the delta-opioid receptor-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), and receptor binding activities were measured. Treating Sprague-Dawley rats with increasing doses of DPDPE (80-160-240-320 micrograms/kg) i.c.v. for 1 to 4 days resulted in a time-dependent increase in the AD50 of DPDPE to elicit an antinociceptive response. When delta-receptor binding was determined by using [3H]DPDPE, a 40-50% decrease in binding in the midbrain and cortex, and 25-35% decrease in binding in the striatum were observed after 3 or 4 days of DPDPE treatment. Scatchard analysis of the [3H]DPDPE saturation binding data revealed a decrease in Bmax values and no significant change in Kd values. To our surprise, when mu-receptor binding was determined by using [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO), a 10-15% decrease in binding was also observed in the midbrain and cortex after 4 days of DPDPE treatment. Our conclusion is that chronic DPDPE treatment preferentially reduces delta-opioid receptor binding activity. Its minor effect on the mu-opioid receptor maybe due to an interaction between delta cx and mu cx binding sites.
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors.forename: P L
authors.initials: PL
authors.lastname: Tao
authors.forename: C L
authors.initials: CL
authors.lastname: Tsai
authors.forename: L R
authors.initials: LR
authors.lastname: Chang
authors.forename: H H
authors.initials: HH
authors.lastname: Loh
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology*; D004745:Enkephalins / Q000494:pharmacology; D005048:Etorphine / Q000494:pharmacology; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
chemical_list: D000700:Analgesics; D004745:Enkephalins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005048:Etorphine; D016308:Enkephalin, Leucine-2-Alanine