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Morphine Desensitization, Internalization, and Down-Regulation of the µ Opioid Receptor Is Facilitated by Serotonin 5-Hydroxytryptamine_2A Receptor Coactivation

Molecular Pharmacology Group, Neuroscience and Molecular Pharmacology, Faculty of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (J.F.L.-G., G.M.); and Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Cientificas-El Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain (M.T.V.)

Analysis of the distribution of mRNA encoding the serotonin (5-hydroxytryptamine) 5-HT_2A receptor and the µ opioid peptide receptor in rat brain demonstrated their coexpression in neurons in several distinct regions. These regions included the periaqueductal gray, an area that plays an important role in morphine-induced analgesia but also in the development of tolerance to morphine. To explore potential cross-regulation between these G protein-coupled receptors, the human µ opioid peptide receptor was expressed stably and constitutively in Flp-In T-REx human embryonic kidney 293 cells that harbored the human 5-HT_2A receptor at the inducible Flp-In locus. In the absence of the 5-HT_2A receptor, pretreatment with the enkephalin agonist [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin but not with the alkaloid agonist morphine produced desensitization, internalization, and down-regulation of the µ opioid peptide receptor. Induction of 5-HT_2A receptor expression in these cells resulted in up-regulation of µ opioid peptide receptor levels that was blocked by both a 5-HT_2A receptor inverse agonist and selective inhibition of signaling via G_q/G₁₁ G proteins. After induction of the 5-HT_2A receptor, coaddition of 5-HT with morphine now also resulted in desensitization, receptor internalization, and down-regulation of the µ opioid peptide receptor. It has been argued that enhancement of µ opioid peptide receptor internalization in response to morphine would limit the development of tolerance without limiting analgesia. These data suggest that selective activation of the 5-HT_2A receptor in concert with treatment with morphine might achieve this aim.

Address correspondence to: Dr. Graeme Milligan, Davidson Bldg., University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom. E-mail: g.milligan{at}bio.gla.ac.uk

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