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Biotech / Medical : ACADIA Pharmaceuticals Inc (ACAD)

ACAD 22.14

-2.5%

9:30 AM EST

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To: scaram(o)uche who wrote (472)	8/21/2008 11:13:01 AM
From: tuck	of 588

[Morphine desensitization, internalization and down-regulation of the mu opioid receptor is facilitated by serotonin 5-HT2A receptor co-activation] Just parking, no direct relevance at the moment. >>Mol Pharmacol. 2008 Aug 14. [Epub ahead of print] Morphine desensitization, internalization and down-regulation of the mu opioid receptor is facilitated by serotonin 5-HT2A receptor co-activation. Lopez-Gimenez JF, Vilaro MT, Milligan G. University of Glasgow. Analysis of the distribution of mRNA encoding the 5-HT2A 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 HEK293 cells that harbored the human 5-HT2A receptor at the inducible Flp-In locus. In the absence of the 5-HT2A receptor pre-treatment with the enkephalin agonist DAMGO but not with the alkaloid agonist morphine produced desensitization, internalization and down-regulation of the mu opioid peptide receptor. Induction of 5-HT2A receptor expression in these cells resulted in up-regulation of mu opioid peptide receptor levels that was blocked by both a 5-HT2A receptor inverse agonist and selective inhibition of signalling via Galphaq/Galpha11 G proteins. Following induction of the 5-HT2A 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-HT2A receptor in concert with treatment with morphine might achieve this aim.<< Full text freebie: molpharm.aspetjournals.org Cheers, Tuck

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