J.L. and J.D.L. contributed equally to this study.
μ-Opioid receptor desensitization: homologous or heterologous?
Article first published online: 24 SEP 2012
© 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 36, Issue 12, pages 3636–3642, December 2012
How to Cite
Llorente, J., Lowe, J. D., Sanderson, H. S., Tsisanova, E., Kelly, E., Henderson, G. and Bailey, C. P. (2012), μ-Opioid receptor desensitization: homologous or heterologous?. European Journal of Neuroscience, 36: 3636–3642. doi: 10.1111/ejn.12003
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- Issue published online: 17 DEC 2012
- Article first published online: 24 SEP 2012
- Manuscript Accepted: 15 AUG 2012
- Manuscript Revised: 14 AUG 2012
- Manuscript Received: 8 MAY 2012
- National Institute on Drug Abuse (USA) international collaboration. Grant Number: DA 020836
- Medical Research Council (UK). Grant Number: G0701486
- Wellcome Trust
- opioid receptor;
There is considerable controversy over whether μ-opioid receptor (MOPr) desensitization is homologous or heterologous and over the mechanisms underlying such desensitization. In different cell types MOPr desensitization has been reported to involve receptor phosphorylation by various kinases, including G-protein-coupled receptor kinases (GRKs), second messenger and other kinases as well as perturbation of the MOPr effector pathway by GRK sequestration of G protein βγ subunits or ion channel modulation. Here we report that in brainstem locus coeruleus (LC) neurons prepared from relatively mature rats (5–8 weeks old) rapid MOPr desensitization induced by the high-efficacy opioid peptides methionine enkephalin and DAMGO was homologous and not heterologous to α2-adrenoceptors and somatostatin SST2 receptors. Given that these receptors all couple through G proteins to the same set of G-protein inwardly rectifying (GIRK) channels it is unlikely therefore that in mature neurons MOPr desensitization involves G protein βγ subunit sequestration or ion channel modulation. In contrast, in slices from immature animals (less than postnatal day 20), MOPr desensitization was observed to be heterologous and could be downstream of the receptor. Heterologous MOPr desensitization was not dependent on protein kinase C or c-Jun N-terminal kinase activity, but the change from heterologous to homologous desensitization with age was correlated with a decrease in the expression levels of GRK2 in the LC and other brain regions. The observation that the mechanisms underlying MOPr desensitization change with neuronal development is important when extrapolating to the mature brain results obtained from experiments on expression systems, cell lines and immature neuronal preparations.