Received for publication April 29, 2008.
Revised July 22, 2008.
Accepted for publication July 29, 2008.

Morphine desensitization, internalization and down-regulation of the mu opioid receptor is facilitated by serotonin 5-HT_2A receptor co-activation

Abstract

Analysis of the distribution of mRNA encoding the 5-HT_2A 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-HT_2A receptor at the inducible Flp-In locus. In the absence of the 5-HT_2A 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-HT_2A receptor expression in these cells resulted in up-regulation of mu opioid peptide receptor levels that was blocked by both a 5-HT_2A receptor inverse agonist and selective inhibition of signalling via G_q/G₁₁ G proteins. Following induction of the 5-HT_2A 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_2A receptor in concert with treatment with morphine might achieve this aim.

Key words: Serotonin, Opioid, Desensitization/uncoupling, Sequestration/Internalization, Opioids