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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 Aug;86(16):6393–6397. doi: 10.1073/pnas.86.16.6393

Selective changes in mu opioid receptor properties induced by chronic morphine exposure.

L L Werling 1, P N McMahon 1, B M Cox 1
PMCID: PMC297846  PMID: 2548212

Abstract

Chronic infusion of morphine to guinea pigs produced selective changes in mu agonist binding properties in cerebrocortical membrane preparations. Employing the mu-selective opioid agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) in direct binding studies and in competition of labeled antagonist binding, we found that the major changes were a decrease in the number of sites with high affinity for agonist, a small reduction in total receptor number, and a loss in the ability of guanosine 5'-[gamma-thio]triphosphate to regulate binding. A fraction of high-affinity mu receptors appeared to retain their high affinity for agonist and their sensitivity to guanine nucleotide analogue after the induction of morphine tolerance, possibly because the morphine concentrations achieved in brain were insufficient to uncouple all mu receptors from associated guanine nucleotide-binding regulatory proteins. Some membrane preparations were treated with pertussis toxin, which has been shown to functionally uncouple mu opioid receptors from their effector systems. In these preparations, a single agonist-affinity state of the receptor was observed. The apparent dissociation constant for this affinity state in pertussis toxin-treated membranes was similar to the lower-affinity state observed in preparations from morphine-tolerant animals. In contrast to the changes observed at mu opioid binding sites, no significant changes in agonist affinity or binding density were observed for selective delta or kappa agonists, consistent with the development of selective tolerance at mu receptors.

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Selected References

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  1. Aghajanian G. K., Wang Y. Y. Pertussis toxin blocks the outward currents evoked by opiate and alpha 2-agonists in locus coeruleus neurons. Brain Res. 1986 Apr 23;371(2):390–394. doi: 10.1016/0006-8993(86)90382-3. [DOI] [PubMed] [Google Scholar]
  2. Aub D. L., Frey E. A., Sekura R. D., Cote T. E. Coupling of the thyrotropin-releasing hormone receptor to phospholipase C by a GTP-binding protein distinct from the inhibitory or stimulatory GTP-binding protein. J Biol Chem. 1986 Jul 15;261(20):9333–9340. [PubMed] [Google Scholar]
  3. Carroll J. A., Shaw J. S., Wickenden A. D. The physiological relevance of low agonist affinity binding at opioid mu-receptors. Br J Pharmacol. 1988 Jun;94(2):625–631. doi: 10.1111/j.1476-5381.1988.tb11569.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chavkin C., Goldstein A. Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus. Proc Natl Acad Sci U S A. 1984 Nov;81(22):7253–7257. doi: 10.1073/pnas.81.22.7253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Christie M. J., Williams J. T., North R. A. Cellular mechanisms of opioid tolerance: studies in single brain neurons. Mol Pharmacol. 1987 Nov;32(5):633–638. [PubMed] [Google Scholar]
  6. Crain S. M., Crain B., Makman M. H. Pertussis toxin blocks depressant effects of opioid, monoaminergic and muscarinic agonists on dorsal-horn network responses in spinal cord-ganglion cultures. Brain Res. 1987 Jan 1;400(1):185–190. doi: 10.1016/0006-8993(87)90670-6. [DOI] [PubMed] [Google Scholar]
  7. Goldstein A., Schulz R. Morphine-tolerant longitudinal muscle strip from guinea-pig ileum. Br J Pharmacol. 1973 Aug;48(4):655–666. doi: 10.1111/j.1476-5381.1973.tb08254.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Höllt V., Dum J., Bläsig J., Schubert P., Herz A. Comparison of in vivo and in vitro parameters of opiate receptor binding in naive and tolerant dependent rodents. Life Sci. 1975 Jun 15;16(12):1823–1828. doi: 10.1016/0024-3205(75)90284-2. [DOI] [PubMed] [Google Scholar]
  9. Klee W. A., Streaty R. A. Narcotic receptor sites in morphine-dependent rats. Nature. 1974 Mar 1;248(5443):61–63. doi: 10.1038/248061a0. [DOI] [PubMed] [Google Scholar]
  10. Kurose H., Katada T., Amano T., Ui M. Specific uncoupling by islet-activating protein, pertussis toxin, of negative signal transduction via alpha-adrenergic, cholinergic, and opiate receptors in neuroblastoma x glioma hybrid cells. J Biol Chem. 1983 Apr 25;258(8):4870–4875. [PubMed] [Google Scholar]
  11. Law P. Y., Hom D. S., Loh H. H. Opiate receptor down-regulation and desensitization in neuroblastoma X glioma NG108-15 hybrid cells are two separate cellular adaptation processes. Mol Pharmacol. 1983 Nov;24(3):413–424. [PubMed] [Google Scholar]
  12. Mucha R. F., Kalant H. Naloxone prevention of morphine LDR curve flattening associated with high-dose tolerance. Psychopharmacology (Berl) 1981;75(2):132–133. doi: 10.1007/BF00432174. [DOI] [PubMed] [Google Scholar]
  13. Munson P. J., Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. doi: 10.1016/0003-2697(80)90515-1. [DOI] [PubMed] [Google Scholar]
  14. ORAHOVATS P. D., WINTER C. A., LEHMAN E. G. The effect of N-allylnormorphine upon the development of tolerance to morphine in the albino rat. J Pharmacol Exp Ther. 1953 Dec;109(4):413–416. [PubMed] [Google Scholar]
  15. Puttfarcken P. S., Werling L. L., Cox B. M. Effects of chronic morphine exposure on opioid inhibition of adenylyl cyclase in 7315c cell membranes: a useful model for the study of tolerance at mu opioid receptors. Mol Pharmacol. 1988 May;33(5):520–527. [PubMed] [Google Scholar]
  16. Rogers N. F., el-Fakahany E. E. Intact brain cells: a novel model system for studying opioid receptor binding. Life Sci. 1985 Jul 29;37(4):307–314. doi: 10.1016/0024-3205(85)90500-4. [DOI] [PubMed] [Google Scholar]
  17. Rogers N. F., el-Fakahany E. Morphine-induced opioid receptor down-regulation detected in intact adult rat brain cells. Eur J Pharmacol. 1986 May 27;124(3):221–230. doi: 10.1016/0014-2999(86)90223-2. [DOI] [PubMed] [Google Scholar]
  18. Schulz R., Wüster M., Herz A. Differentiation of opiate receptors in the brain by the selective development of tolerance. Pharmacol Biochem Behav. 1981 Jan;14(1):75–79. doi: 10.1016/0091-3057(81)90105-2. [DOI] [PubMed] [Google Scholar]
  19. Schulz R., Wüster M., Krenss H., Herz A. Lack of cross-tolerance on multiple opiate receptors in the mouse vas deferens. Mol Pharmacol. 1980 Nov;18(3):395–401. [PubMed] [Google Scholar]
  20. Sullivan K. A., Miller R. T., Masters S. B., Beiderman B., Heideman W., Bourne H. R. Identification of receptor contact site involved in receptor-G protein coupling. Nature. 1987 Dec 24;330(6150):758–760. doi: 10.1038/330758a0. [DOI] [PubMed] [Google Scholar]
  21. Tao P. L., Law P. Y., Loh H. H. Decrease in delta and mu opioid receptor binding capacity in rat brain after chronic etorphine treatment. J Pharmacol Exp Ther. 1987 Mar;240(3):809–816. [PubMed] [Google Scholar]
  22. Werling L. L., McMahon P. N., Cox B. M. Selective tolerance at mu and kappa opioid receptors modulating norepinephrine release in guinea pig cortex. J Pharmacol Exp Ther. 1988 Dec;247(3):1103–1106. [PubMed] [Google Scholar]
  23. Werling L. L., Puttfarcken P. S., Cox B. M. Multiple agonist-affinity states of opioid receptors: regulation of binding by guanyl nucleotides in guinea pig cortical, NG108-15, and 7315c cell membranes. Mol Pharmacol. 1988 Apr;33(4):423–431. [PubMed] [Google Scholar]
  24. Zarr G. D., Werling L. L., Brown S. R., Cox B. M. Opioid ligand binding sites in the spinal cord of the guinea-pig. Neuropharmacology. 1986 May;25(5):471–480. doi: 10.1016/0028-3908(86)90170-x. [DOI] [PubMed] [Google Scholar]

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