TY - JOUR T1 - Morphine Desensitization, Internalization, and Down-Regulation of the μ Opioid Receptor Is Facilitated by Serotonin 5-Hydroxytryptamine<sub>2A</sub> Receptor Coactivation JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1278 LP - 1291 DO - 10.1124/mol.108.048272 VL - 74 IS - 5 AU - Juan F. Lopez-Gimenez AU - M. Teresa Vilaró AU - Graeme Milligan Y1 - 2008/11/01 UR - http://molpharm.aspetjournals.org/content/74/5/1278.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -