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Abstract
BACKGROUND AND PURPOSEThe 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 APPROACHMOR 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 RESULTSMORs 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 IMPLICATIONSAgonist-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 ARTICLESThis 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
Highlights
The μ-opioid receptor (MOR), a GPCR, rapidly desensitizes in response to various opioid agonists
All of the cells we identified as dopaminergic exhibited a response that was mediated by presynaptic opioid receptors on GABAergic nerve terminals
Whole-cell patch-clamp recordings were taken from dopaminergic neurons in the mouse ventral tegmental area (VTA). Miniature IPSCs (mIPSCs) were recorded, in the presence of tetrodotoxin, in order to isolate any effects of MOR agonists to the nerve terminals of GABAergic afferents (Bergevin et al, 2002)
Summary
The μ-opioid receptor (MOR), a GPCR (nomenclature follows Alexander et al, 2013a), rapidly desensitizes in response to various opioid agonists. The precise molecular mechanism by which this desensitization takes place depends on the opioid agonist used to activate the receptor. The vast majority of previous studies examining agonistinduced desensitization of MORs have examined those receptors located on cell bodies of recombinant expression systems (e.g. HEK293 cells) or on cell bodies and dendrites (somatodendritically) of neurons. In common with most other GPCRs, there is widespread expression of MORs at nerve terminals of neurons in the mammalian CNS. AND PURPOSE The majority of studies examining desensitization of the μ-opioid receptor (MOR) have examined those located at cell bodies. This study is designed to investigate agonist-induced MOR desensitization at nerve terminals in the mouse ventral tegmental area (VTA). Presynaptic MOR function was isolated from postsynaptic function and the functional selectivity, time-dependence and mechanisms of agonist-induced MOR desensitization were examined
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