Differential down- and up-regulation of rat brain opioid receptor types and subtypes by buprenorphine

MM Belcheva, J Barg, RJ McHale, S Dawn, MT Ho, E Ignatova and CJ Coscia

E. A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, Missouri 63104.

The induction of opioid receptor adaptation by mixed agonist- antagonists such as buprenorphine has not been investigated. To this end, neonatal rats were given injections of buprenorphine (0.1-2.5 mg/kg/day) and mu binding (Kd and Bmax) to brain membranes was measured with [3H][D-Ala2,MePhe4,Gly-ol5]enkephalin. At doses of buprenorphine of > or = 0.5 mg/kg, mu sites were reduced 47-75%, without changes in affinity. Chronic administration of the structurally related partial agonist diprenorphine (2.5-75 mg/kg) failed to alter mu binding. Apparent loss of sites due to receptor blockade by residual buprenorphine was ruled out by several lines of evidence. Bmax values for delta ([3H][D-Ser2,L-Leu5]enkephalyl-Thr) and kappa ([3H]U69593) binding were elevated 1.9-4.2-fold by buprenorphine treatment. In adult rats buprenorphine (0.5-2.5 mg/kg) reduced mu-opioid binding to forebrain membranes dose dependently, by 25-77%. [3H][D-Ser2,L-Leu5] Enkephalyl-Thr-labeled delta subtype receptors and kappa sites in adult forebrain membranes were up-regulated 2-3-fold. The delta subtype receptors that bind [3H][D-Pen2,D-Pen5]enkephalin in neonatal or adult brain membranes were unaffected by 0.5-2.5 mg/kg buprenorphine treatment. Down-regulation (70-74%) of mu sites and up-regulation (1.9- 6.7 fold) of delta and kappa receptors were also observed in synaptic plasma membrane-enriched and microsomal fractions from buprenorphine- treated adult rat brain. Because agonist-induced opioid receptor down- regulation is difficult to elicit in adult mammalian brain, these data indicate that buprenorphine is a useful tool to study brain opioid receptor adaptation in vivo.

Volume 44, Issue 1, pp. 173-179, 07/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				Y. Chen, C. Chen, Y. Wang, and L.-Y. Liu-Chen Ligands Regulate Cell Surface Level of the Human {kappa} Opioid Receptor by Activation-Induced Down-Regulation and Pharmacological Chaperone-Mediated Enhancement: Differential Effects of Nonpeptide and Peptide Agonists J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 765 - 775. [Abstract] [Full Text] [PDF]

				P. Huang, G. B. Kehner, A. Cowan, and L.-Y. Liu-Chen Comparison of Pharmacological Activities of Buprenorphine and Norbuprenorphine: Norbuprenorphine Is a Potent Opioid Agonist J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 688 - 695. [Abstract] [Full Text]

				P. A. Zaki, D. E. Keith Jr., G. A. Brine, F. I. Carroll, and C. J. Evans Ligand-Induced Changes in Surface {micro}-Opioid Receptor Number: Relationship to G Protein Activation? J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 1127 - 1134. [Abstract] [Full Text]

				G. Bot, A. D. Blake, S. Li, and T. Reisine Mutagenesis of the Mouse Delta Opioid Receptor Converts (-)-Buprenorphine from a Partial Agonist to an Antagonist J. Pharmacol. Exp. Ther., January 1, 1998; 284(1): 283 - 290. [Abstract] [Full Text]