Opioid agonists are the best therapy for moderate to severe pain, but clinical use is limited due to the development of tolerance and dependence. For the first time, Bailey and co-workers have demonstrated functional selectivity for agonist-induced desensitization of µ-opioid receptors (MOR) in mature rat locus coeruleus neurons. Native MORs are differentially desensitized through separate, agonist-dependent signalling pathways; desensitization of the morphine-occupied receptor occurs via a protein kinase C alpha-dependent pathway while [D-Ala2, N-MePhe4, Gly-ol]enkephalin-mediated desensitization is via a G protein receptor kinase subtype 2-dependent mechanism. These results suggest that MORs adopt separate conformational states that either result in different efficiencies of G protein activation or access to phosphorylation by desensitization machinery (e.g. protein kinase C alpha or G protein receptor kinase subtype 2). Further study of the interaction of protein kinase C with MORs in native neurons will enhance our understanding of agonist-induced functional selectivity for desensitization at MORs and provide important insights into how to selectively modulate agonist efficacy to enhance therapeutic capabilities of opioid drugs.