AbstractThere is considerable controversy over whether μ‐opioid receptor (MOPr) desensitization is homologous or heterologous and over the mechanisms underlying such desensitization. In different cell typesMOPr desensitization has been reported to involve receptor phosphorylation by various kinases, includingG‐protein‐coupled receptor kinases (GRKs), second messenger and other kinases as well as perturbation of theMOPr effector pathway byGRKsequestration ofGprotein 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) rapidMOPr desensitization induced by the high‐efficacy opioid peptides methionine enkephalin andDAMGOwas homologous and not heterologous to α2‐adrenoceptors and somatostatinSST2receptors. Given that these receptors all couple throughGproteins to the same set ofG‐protein inwardly rectifying (GIRK) channels it is unlikely therefore that in mature neuronsMOPr desensitization involvesGprotein 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. HeterologousMOPr desensitization was not dependent on protein kinaseCor c‐JunN‐terminal kinase activity, but the change from heterologous to homologous desensitization with age was correlated with a decrease in the expression levels ofGRK2 in theLCand other brain regions. The observation that the mechanisms underlyingMOPr 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.