Functional selectivity and time‐dependence of μ‐opioid receptor desensitization at nerve terminals in the mouse ventral tegmental area

• Published in: British journal of pharmacology Vol. 172; no. 2; pp. 469 - 481
• Main Authors: Lowe, J D, Bailey, C P
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2015
• Subjects: Action Potentials; Analgesics, Opioid - pharmacology; Animals; desensitization; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - physiology; Enkephalin, Ala-MePhe-Gly- - pharmacology; Enkephalin, Methionine - pharmacology; GABAergic Neurons - drug effects; GABAergic Neurons - physiology; GPCR kinase (GRK); In Vitro Techniques; Male; Mice, Inbred C57BL; morphine; Morphine - pharmacology; nerve terminal; opiate; opioid; PKC; Protein Kinase C - physiology; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - physiology; Themed Section: Opioids: New Pathways to Functional Selectivity; tolerance; ventral tegmental area (VTA); Ventral Tegmental Area - physiology; nerve terminal; opioid; PKC; GPCR kinase (GRK); desensitization; tolerance; morphine; opiate; ventral tegmental area (VTA)
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12605

Background and Purpose The majority of studies examining desensitization of the μ‐opioid receptor (MOR) have examined those located at cell bodies. However, MORs are extensively expressed at nerve terminals throughout the mammalian nervous system. This study is designed to investigate agonist‐induced MOR desensitization at nerve terminals in the mouse ventral tegmental area (VTA). Experimental Approach MOR function was measured in mature mouse brain slices containing the VTA using whole‐cell patch‐clamp electrophysiology. Presynaptic MOR function was isolated from postsynaptic function and the functional selectivity, time‐dependence and mechanisms of agonist‐induced MOR desensitization were examined. Key Results MORs located at GABAergic nerve terminals in the VTA were completely resistant to rapid desensitization induced by the high‐efficacy agonists DAMGO and Met‐enkephalin. MORs located postsynaptically on GABAergic cell bodies readily underwent rapid desensitization in response to DAMGO. However, after prolonged (>7 h) treatment with Met‐enkephalin, profound homologous MOR desensitization was observed. Morphine could induce rapid MOR desensitization at nerve terminals when PKC was activated. Conclusions and Implications Agonist‐induced MOR desensitization in GABAergic neurons in the VTA is compartment‐selective as well as agonist‐selective. When MORs are located at cell bodies, higher‐efficacy agonists induce greater levels of rapid desensitization than lower‐efficacy agonists. However, the converse is true at nerve terminals where agonists that induce MOR desensitization via PKC are capable of rapid agonist‐induced desensitization while higher‐efficacy agonists are not. MOR desensitization induced by higher‐efficacy agonists at nerve terminals only takes place after prolonged receptor activation. Linked Articles This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2