Functional selectivity and time-dependence of μ-opioid receptor desensitization at nerve terminals in the mouse ventral tegmental area.
OBJECTIVE
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).


METHODS
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.


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
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.


BACKGROUND
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.
Department of Pharmacy & Pharmacology, University of Bath, Bath, UK; School of Physiology & Pharmacology, University of Bristol, Bristol, UK.
J D
JD
Lowe
C P
CP
Bailey
D000200:Action Potentials; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000502:physiology*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004744:Enkephalin, Methionine; D009020:Morphine; D011493:Protein Kinase C
GPCR kinase (GRK); PKC; desensitization; morphine; nerve terminal; opiate; opioid; tolerance; ventral tegmental area (VTA)