Morphine desensitization, internalization and down-regulation of the μ opioid receptor is facilitated by serotonin 5-hydroxytryptamine2A receptor co-activation

Lopez-Gimenez, J. F., Vilaro, M. T. and Milligan, G. (2008) Morphine desensitization, internalization and down-regulation of the μ opioid receptor is facilitated by serotonin 5-hydroxytryptamine2A receptor co-activation. Molecular Pharmacology, 74(5), pp. 1278-1291. (doi: 10.1124/mol.108.048272) (PMID:18703670)

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Publisher's URL: http://dx.doi.org/10.1124/mol.108.048272

Abstract

Analysis of the distribution of mRNA encoding the 5-HT<sub>2A</sub> receptor and the mu opioid peptide receptor in rat brain demonstrated their co-expression in neurones in a number of distinct regions. These included the periacqueductal grey, 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 mu opioid peptide receptor was expressed stably and constitutively in Flp-In T-REx human embryonic kidney 293 cells that harbored the human 5-HT<sub>2A</sub> receptor at the inducible Flp-In locus. In the absence of the 5-HT<sub>2A</sub> receptor pre-treatment with the enkephalin agonist {Delta}Ala<sup>2</sup>,<i>N</i>-Me-Phe<sup>4</sup>,Gly<sup>5</sup>-o1]-enkephalin but not with the alkaloid agonist morphine produced desensitization, internalization and down-regulation of the mu opioid peptide receptor. Induction of 5-HT<sub>2A</sub> receptor expression in these cells resulted in up-regulation of mu opioid peptide receptor levels that was blocked by both a 5-HT<sub>2A</sub> receptor inverse agonist and selective inhibition of signalling via G{alpha}<sub>q</sub>/G{alpha}<sub>11</sub> G proteins. Following induction of the 5-HT<sub>2A</sub> receptor co-addition of 5-HT with morphine now also resulted in each of desensitization, receptor internalization and down-regulation of the mu opioid peptide receptor. It has been argued that enhancement of mu 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<sub>2A</sub> receptor in concert with treatment with morphine might achieve this aim

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lopez-Gimenez, Dr Juan and Milligan, Professor Graeme
Authors: Lopez-Gimenez, J. F., Vilaro, M. T., and Milligan, G.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
College/School:College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Molecular Pharmacology
Publisher:American Association of Immunologists
ISSN:0026-895X
ISSN (Online):1550-6606
Published Online:14 August 2008
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