G-Protein-Gated Potassium Channels Containing Kir3.2 and Kir3.3 Subunits Mediate the Acute Inhibitory Effects of Opioids on Locus Ceruleus Neurons

Maria Torrecilla, Cheryl L. Marker, Stephanie C. Cintora, Markus Stoffel, John Williams, Kevin Wickman

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Acute opioid administration causes hyperpolarization of locus ceruleus (LC) neurons. A G-protein-gated, inwardly rectifying potassium (GIRK/KG) conductance and a cAMP-dependent cation conductance have both been implicated in this effect; the relative contribution of each conductance remains controversial. Here, the contribution of KG channels to the inhibitory effects of opioids on LC neurons was examined using mice that lack the KG channel subunits Kir3.2 and Kir3.3. Resting membrane potentials of LC neurons in brain slices from Kir3.2 knock-out, Kir3.3 knock-out, and Kir3.2/3.3 double knock-out mice were depolarized by 15-20 mV relative to LC neurons from wild-type mice. [Met]5enkephalin-induced hyperpolarization and whole-cell current were reduced by 40% in LC neurons from Kir3.2 knock-out mice and by 80% in neurons from Kir3.2/3.3 double knock-out mice. The small opioid-sensitive current observed in LC neurons from Kir3.2/3.3 double knock-out mice was virtually eliminated with the nonselective potassium channel blockers barium and cesium. We conclude that the acute opioid inhibition of LC neurons is mediated primarily by the activation of G-protein-gated potassium channels and that the cAMP-dependent cation conductance does not contribute significantly to this effect.

Original languageEnglish (US)
Pages (from-to)4328-4334
Number of pages7
JournalJournal of Neuroscience
Volume22
Issue number11
StatePublished - Jun 1 2002

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G Protein-Coupled Inwardly-Rectifying Potassium Channels
Locus Coeruleus
GTP-Binding Proteins
Opioid Analgesics
Neurons
Knockout Mice
Cations
Potassium Channel Blockers
Cesium
Potassium Channels
Barium
Membrane Potentials
Potassium

Keywords

  • Addiction
  • GIRK
  • Kir3.0
  • Locus ceruleus
  • Met-enkephalin
  • Mouse knock-out
  • Opioid receptor
  • Potassium channel blockers
  • Tolerance
  • Whole-cell recording

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

G-Protein-Gated Potassium Channels Containing Kir3.2 and Kir3.3 Subunits Mediate the Acute Inhibitory Effects of Opioids on Locus Ceruleus Neurons. / Torrecilla, Maria; Marker, Cheryl L.; Cintora, Stephanie C.; Stoffel, Markus; Williams, John; Wickman, Kevin.

In: Journal of Neuroscience, Vol. 22, No. 11, 01.06.2002, p. 4328-4334.

Research output: Contribution to journalArticle

Torrecilla, Maria ; Marker, Cheryl L. ; Cintora, Stephanie C. ; Stoffel, Markus ; Williams, John ; Wickman, Kevin. / G-Protein-Gated Potassium Channels Containing Kir3.2 and Kir3.3 Subunits Mediate the Acute Inhibitory Effects of Opioids on Locus Ceruleus Neurons. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 11. pp. 4328-4334.
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N2 - Acute opioid administration causes hyperpolarization of locus ceruleus (LC) neurons. A G-protein-gated, inwardly rectifying potassium (GIRK/KG) conductance and a cAMP-dependent cation conductance have both been implicated in this effect; the relative contribution of each conductance remains controversial. Here, the contribution of KG channels to the inhibitory effects of opioids on LC neurons was examined using mice that lack the KG channel subunits Kir3.2 and Kir3.3. Resting membrane potentials of LC neurons in brain slices from Kir3.2 knock-out, Kir3.3 knock-out, and Kir3.2/3.3 double knock-out mice were depolarized by 15-20 mV relative to LC neurons from wild-type mice. [Met]5enkephalin-induced hyperpolarization and whole-cell current were reduced by 40% in LC neurons from Kir3.2 knock-out mice and by 80% in neurons from Kir3.2/3.3 double knock-out mice. The small opioid-sensitive current observed in LC neurons from Kir3.2/3.3 double knock-out mice was virtually eliminated with the nonselective potassium channel blockers barium and cesium. We conclude that the acute opioid inhibition of LC neurons is mediated primarily by the activation of G-protein-gated potassium channels and that the cAMP-dependent cation conductance does not contribute significantly to this effect.

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