QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.050625v2 jpet.103.050625v3 306/1/179    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ko, M. C. H. Articles by Traynor, J. R. Search for Related Content PubMed PubMed Citation Articles by Ko, M. C. H. Articles by Traynor, J. R.

NEUROPHARMACOLOGY

Studies of µ-, -, and -Opioid Receptor Density and G Protein Activation in the Cortex and Thalamus of Monkeys

Departments of Anesthesiology (N.N.N.) and Pharmacology (M.C.H.K., H.L., C.H., M.J.C., H.F.S., J.H.W., J.R.T.), The University of Michigan Medical School, Ann Arbor, Michigan

The aim of this study was to investigate the relative density of µ-, -, and -opioid receptors (MOR, KOR, and DOR) and guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding stimulated by full agonists in cortical and thalamic membranes of monkeys. The binding parameters [B_max (femtomoles per milligram)/K_d (nanomolar)] were as follows: [³H][D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO) (MOR; 80/0.7), [³H]U69593 [(5,7,8)-(–)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide] (KOR; 116/1.3), and [³H][D-Pen²,D-Pen⁵]-enkephalin (DPDPE) (DOR; 87/1.3) in the cortex; [³H]DAMGO (147/0.9), [³H]U69593 (75/2.5), and [³H]DPDPE (22/2.0) in the thalamus. The relative proportions of MOR, KOR, and DOR in the cortex were 28, 41, and 31% and in the thalamus were 60, 31, and 9%. Full selective opioid agonists, DAMGO (EC₅₀ = 532–565 nM) and U69593 (EC₅₀ = 80–109 nM) stimulated [³⁵S]GTPS binding in membranes of cortex and thalamus, whereas SNC80 [(+)-4-[(R)--((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethyl-benzamide] (DOR; EC₅₀ = 68 nM) was only active in cortical membranes. The magnitudes of [³⁵S]GTPS binding stimulated by these agonists were similar in the cortex, ranging from 17 to 25% over basal binding. In the thalamus, DAMGO and U69593 increased [³⁵S]GTPS binding by 44 and 23% over basal, respectively. Opioid agonist-stimulated [³⁵S]GTPS binding was blocked selectively by antagonists for MOR, KOR, and DOR. The amount of G protein activated by agonists was highly proportional to the relative receptor densities in both regions. These results distinguish the ability of opioid agonists to activate G proteins and provide a functional correlate of ligand-binding experiments in the monkey brain. In particular, the relative densities of opioid receptor binding sites in the two brain areas reflect their functional roles in the pharmacological actions of opioids in the central nervous system of primates.

Address correspondence to: Dr. M. C. Holden Ko, Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, MI 48109-0632. E-mail: mko{at}umich.edu

This article has been cited by other articles:

				B. G. Oertel, M. Kettner, K. Scholich, C. Renne, B. Roskam, G. Geisslinger, P. H. Schmidt, and J. Lotsch A Common Human {micro}-Opioid Receptor Genetic Variant Diminishes the Receptor Signaling Efficacy in Brain Regions Processing the Sensory Information of Pain J. Biol. Chem., March 6, 2009; 284(10): 6530 - 6535. [Abstract] [Full Text] [PDF]

				H. Xie, J. H. Woods, J. R. Traynor, and M.-C. Ko The Spinal Antinociceptive Effects of Endomorphins in Rats: Behavioral and G Protein Functional Studies Anesth. Analg., June 1, 2008; 106(6): 1873 - 1881. [Abstract] [Full Text] [PDF]

				D.-F. Wu, T. Koch, Y.-J. Liang, R. Stumm, S. Schulz, H. Schroder, and V. Hollt Membrane Glycoprotein M6a Interacts with the {micro}-Opioid Receptor and Facilitates Receptor Endocytosis and Recycling J. Biol. Chem., July 27, 2007; 282(30): 22239 - 22247. [Abstract] [Full Text] [PDF]

				M. C. H. Ko, M. F. Divin, H. Lee, J. H. Woods, and J. R. Traynor Differential in Vivo Potencies of Naltrexone and 6beta-Naltrexol in the Monkey J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 772 - 779. [Abstract] [Full Text] [PDF]

				P. S. Talbot, R. Narendran, E. R. Butelman, Y. Huang, K. Ngo, M. Slifstein, D. Martinez, M. Laruelle, and D.-R. Hwang 11C-GR103545, a Radiotracer for Imaging{kappa}-Opioid Receptors In Vivo with PET: Synthesis and Evaluation in Baboons J. Nucl. Med., March 1, 2005; 46(3): 484 - 494. [Abstract] [Full Text] [PDF]