Morphine Desensitization, Internalization, and Down-Regulation of the μ Opioid Receptor Is Facilitated by Serotonin 5-Hydroxytryptamine2AReceptor Coactivation
Open Access
- 14 August 2008
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 74 (5), 1278-1291
- https://doi.org/10.1124/mol.108.048272
Abstract
Analysis of the distribution of mRNA encoding the serotonin (5-hydroxytryptamine) 5-HT2A 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-HT2A receptor at the inducible Flp-In locus. In the absence of the 5-HT2A 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-HT2A receptor expression in these cells resulted in up-regulation of μ opioid peptide receptor levels that was blocked by both a 5-HT2A receptor inverse agonist and selective inhibition of signaling via Gαq/Gα11 G proteins. After induction of the 5-HT2A 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-HT2A receptor in concert with treatment with morphine might achieve this aim.Keywords
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