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

J D Lowe, C P Bailey

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)469-481
Number of pages13
JournalBritish Journal of Pharmacology
Volume172
Issue number2
Early online date28 Jan 2014
DOIs
Publication statusPublished - Jan 2015

Fingerprint

Ventral Tegmental Area
mu Opioid Receptor
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Methionine Enkephalin
GABAergic Neurons
Electrophysiology
Morphine
Opioid Analgesics
Nervous System
Brain
Cell Body

Keywords

  • Action Potentials
  • Analgesics, Opioid
  • Animals
  • Dopaminergic Neurons
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalin, Methionine
  • GABAergic Neurons
  • In Vitro Techniques
  • Male
  • Mice, Inbred C57BL
  • Morphine
  • Protein Kinase C
  • Receptors, Opioid, mu
  • Ventral Tegmental Area
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

@article{a9974ea913f04689b910f087c13136ce,
title = "Functional selectivity and time-dependence of μ-opioid receptor desensitization at nerve terminals in the mouse ventral tegmental area",
abstract = "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.",
keywords = "Action Potentials, Analgesics, Opioid, Animals, Dopaminergic Neurons, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Enkephalin, Methionine, GABAergic Neurons, In Vitro Techniques, Male, Mice, Inbred C57BL, Morphine, Protein Kinase C, Receptors, Opioid, mu, Ventral Tegmental Area, Journal Article, Research Support, Non-U.S. Gov't",
author = "Lowe, {J D} and Bailey, {C P}",
note = "{\circledC} 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.",
year = "2015",
month = "1",
doi = "10.1111/bph.12605",
language = "English",
volume = "172",
pages = "469--481",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Functional selectivity and time-dependence of μ-opioid receptor desensitization at nerve terminals in the mouse ventral tegmental area

AU - Lowe, J D

AU - Bailey, C P

N1 - © 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

KW - Action Potentials

KW - Analgesics, Opioid

KW - Animals

KW - Dopaminergic Neurons

KW - Enkephalin, Ala(2)-MePhe(4)-Gly(5)-

KW - Enkephalin, Methionine

KW - GABAergic Neurons

KW - In Vitro Techniques

KW - Male

KW - Mice, Inbred C57BL

KW - Morphine

KW - Protein Kinase C

KW - Receptors, Opioid, mu

KW - Ventral Tegmental Area

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1111/bph.12605

DO - 10.1111/bph.12605

M3 - Article

VL - 172

SP - 469

EP - 481

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 2

ER -