Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction

JD Alvaro, JB Tatro, JM Quillan, M Fogliano, M Eisenhard, MR Lerner, EJ Nestler and RS Duman

Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.

Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unknown. In this study, we characterize the rat melanocortin-4 receptor (MC4-R) and demonstrate that this receptor is regulated by opiate administration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs (alpha-melanocyte-stimulating hormone = adrenocorticotropic hormone > gamma-melanocyte-stimulating hormone). Expression of MC4-R mRNA was found to be enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated in the behavioral effects of opiates. In contrast, MC1-, MC3-, and MC5-R are expressed at very low or undetectable levels in these brain regions. Chronic administration of morphine (5 days) resulted in a time-dependent down-regulation of MC4-R mRNA expression in the striatum and periaqueductal gray. Expression of MC4-R mRNA was also decreased in the nucleus accumbens/ olfactory tubercle, but this effect was observed after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in melanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not influence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/substantia nigra. In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.

Volume 50, Issue 3, pp. 583-591, 09/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				Y. C. L. Tung, D. Rimmington, S. O'Rahilly, and A. P. Coll Pro-Opiomelanocortin Modulates the Thermogenic and Physical Activity Responses to High-Fat Feeding and Markedly Influences Dietary Fat Preference Endocrinology, November 1, 2007; 148(11): 5331 - 5338. [Abstract] [Full Text] [PDF]

				C. F. Bush, S. V. Jones, A. N. Lyle, K. P. Minneman, K. J. Ressler, and R. A. Hall Specificity of Olfactory Receptor Interactions with Other G Protein-coupled Receptors J. Biol. Chem., June 29, 2007; 282(26): 19042 - 19051. [Abstract] [Full Text] [PDF]

				A Blondet, J Gout, P Durand, M Begeot, and D Naville Expression of the human melanocortin-4 receptor gene is controlled by several members of the Sp transcription factor family J. Mol. Endocrinol., April 1, 2005; 34(2): 317 - 329. [Abstract] [Full Text] [PDF]

				A. Catania, S. Gatti, G. Colombo, and J. M. Lipton Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation Pharmacol. Rev., March 1, 2004; 56(1): 1 - 29. [Abstract] [Full Text] [PDF]

				J. M. Cerda-Reverter, A. Ringholm, H. B. Schioth, and R. E. Peter Molecular Cloning, Pharmacological Characterization, and Brain Mapping of the Melanocortin 4 Receptor in the Goldfish: Involvement in the Control of Food Intake Endocrinology, June 1, 2003; 144(6): 2336 - 2349. [Abstract] [Full Text] [PDF]

				J. D. Alvaro, J. R. Taylor, and R. S. Duman Molecular and Behavioral Interactions Between Central Melanocortins and Cocaine J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 391 - 399. [Abstract] [Full Text] [PDF]

				M. M. Hagan, P. A. Rushing, S. C. Benoit, S. C. Woods, and R. J. Seeley Opioid receptor involvement in the effect of AgRP- (83-132) on food intake and food selection Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2001; 280(3): R814 - R821. [Abstract] [Full Text] [PDF]

				Z. Rahman, S. J. Gold, M. N. Potenza, C. W. Cowan, Y. G. Ni, W. He, T. G. Wensel, and E. J. Nestler Cloning and Characterization of RGS9-2: A Striatal-Enriched Alternatively Spliced Product of the RGS9 Gene J. Neurosci., March 15, 1999; 19(6): 2016 - 2026. [Abstract] [Full Text] [PDF]

				Q.-H. Huang, V. J. Hruby, and J. B. Tatro Systemic alpha -MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release Am J Physiol Regulatory Integrative Comp Physiol, August 1, 1998; 275(2): R524 - R530. [Abstract] [Full Text] [PDF]

				S. J. Gold, Y. G. Ni, H. G. Dohlman, and E. J. Nestler Regulators of G-Protein Signaling (RGS) Proteins: Region-Specific Expression of Nine Subtypes in Rat Brain J. Neurosci., October 15, 1997; 17(20): 8024 - 8037. [Abstract] [Full Text] [PDF]

				Q.-H. Huang, M. L. Entwistle, J. D. Alvaro, R. S. Duman, V. J. Hruby, and J. B. Tatro Antipyretic Role of Endogenous Melanocortins Mediated by Central Melanocortin Receptors during Endotoxin-Induced Fever J. Neurosci., May 1, 1997; 17(9): 3343 - 3351. [Abstract] [Full Text] [PDF]