Update articleMolecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys?
Section snippets
Analgesia induced by opioids and ethanol
Persistent or recurrent pain can degrade the sufferer's quality of life due to discomfort, distraction, and decreased volition, although pain is a crucial alert signal for our body (Wall and Melzack, 1999). Opioids and ethanol have been used widely for relieving pain since ancient times, although the mechanisms of their action remain poorly understood.
Opioids include endogenous peptides, such as enkephalin, endorphin, and dynorphin, and exogenous substances, such as morphine, heroin and
Molecules in the opioid system
A number of molecules in the opioid system have been identified, and their functions have been investigated extensively (Table 1).
Molecules mediating ethanol effects
Ethanol affects the functions of a variety of proteins, such as GIRK channels, some ligand-gated ion channels, some voltage-gated ion channels, and some enzymes (Table 2).
Role of GIRK channel in analgesia
Because analgesia is observed in animals, not in cells, animal models are needed to investigate the roles of molecules in analgesia. In the case of GIRK channels, there are two useful animal models: weaver mutant mice and GIRK2-KO mice.
Conclusion
GIRK channels are functionally coupled with MOR, DOR, and KOR, and are directly activated by ethanol. Recent studies using weaver mutant mice or GIRK2-KO mice have shown the involvement of GIRK channels in analgesia induced either by opioids or ethanol. Opening of the GIRK channels by using opioids or ethanol might lead to analgesia through activation of the descending analgesic pathways in which GIRK channels are expressed. While there is only indirect evidence of the involvement in
Acknowledgements
This work was supported by a research grant from the Cooperative Research Program of the RIKEN Brain Science Institute; Grants-in-Aid for Encouragement of Young Scientists (A), Scientific Research (B) and Scientific Research on Priority Areas (A) and (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Health Sciences Research Grants (Research on Brain Science and Research on Pharmaceutical and Medical Safety) from the Ministry of Health, Labour and Welfare of
References (123)
- et al.
Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory
Cell
(1997) - et al.
Alcohols inhibit a cloned potassium channel at a discrete saturable site. Insights into the molecular basis of general anesthesia
J. Biol. Chem.
(1995) - et al.
Alcohol modulation of calcium-activated potassium channels
Neurochem. Int.
(1999) - et al.
The inward rectifier potassium channel family
Curr. Opin. Neurobiol.
(1995) - et al.
Isolation of a novel tetrapeptide with opiate and antiopiate activity from human brain cortex: Tyr-Pro-Trp-Gly-NH2 (Tyr-W-MIF-1)
Peptides
(1992) - et al.
Chronic ethanol consumption: from neuroadaptation to neurodegeneration
Prog. Neurobiol.
(1998) - et al.
Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice
Brain Res.
(1999) - et al.
Hypertolerance to morphine in Gzα-deficient mice
Brain Res.
(2000) - et al.
Functional couplings of the δ- and the κ-opioid receptors with the G-protein-activated K+ channel
Biochem. Biophys. Res. Commun.
(1995) - et al.
Involvement of G-protein-activated inwardly rectifying K+ (GIRK) channels in opioid-induced analgesia
Neurosci. Res.
(2000)
Unique behavioural phenotypes of recombinant-inbred CXBK mice: partial deficiency of sensitivity to μ- and κ-agonists
Neurosci. Res.
Functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated K+ (GIRK) channel
Brain Res. Mol. Brain Res.
G protein α subunit Gαz couples neurotransmitter receptors to ion channels in sympathetic neurons
Neuron
Distribution and localization of a G protein-coupled inwardly rectifying K+ channel in the rat
FEBS Lett.
Altered nociceptive response in mice deficient in the α1B subunit of the voltage-dependent calcium channel
Mol. Cell Neurosci.
Quantitative autoradiographic mapping of mu-, delta- and kappa-opioid receptors in knockout mice lacking the mu-opioid receptor gene
Brain Res.
Molecular cloning of a mouse G-protein-activated K+ channel (mGIRK1) and distinct distributions of three GIRK (GIRK1, 2 and 3) mRNAs in mouse brain
Biochem. Biophys. Res. Commun.
Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels
J. Biol. Chem.
5-HT3 receptors and the neural actions of alcohols: an increasingly exciting topic
Neurochem. Int.
Opioid receptor mRNA expression in the rat CNS: anatomical and functional implications
Trends Neurosci.
Physico-chemical correlates of alcohol intoxication
Neuropharmacology
Acute effects of ethanol on GABAA and glycine receptor function
Neurochem. Int.
Molecular biology of the opioid receptors: structures, functions and distributions
Neurosci. Res.
ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization
FEBS Lett.
Use of transgenic mice to study voltage-dependent Ca2+ channels
Trends Pharmacol. Sci.
Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the nucleoside transporter
J. Biol. Chem.
Neuronal nicotinic acetylcholine receptors: a new target site of ethanol
Neurochem. Int.
Properties and modulation of mammalian 2P domain K+ channels
Trends Neurosci.
Inwardly rectifying potassium channels
Curr. Opin. Cell Biol.
Generation of dynorphin knockout mice
Brain Res. Mol. Brain Res.
Functional effects of the mouse weaver mutation on G protein-gated inwardly rectifying K+ channels
Neuron
Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry
Annu. Rev. Neurosci.
Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice
J. Pharmacol. Exp. Ther.
Ethanol consumption and behavioral impulsivity are increased in protein kinase Cγ null mutant mice
J. Neurosci.
Ionic channels and their regulation by G protein subunits
Annu. Rev. Physiol.
Morphiceptin (NH4-tyr-pro-phe-pro-COHN2): a potent and specific agonist for morphine μ receptors
Science
Modulation of two cloned potassium channels by 1-alkanols demonstrates different cutoffs
Alcohol Clin. Exp. Res.
Mu-opioid receptor modulation of calcium channel current in periaqueductal grey neurons from C57BL6/J mice and mutant mice lacking MOR-1
Br. J. Pharmacol.
Ethanol selectively blocks a noninactivating K+ current expressed in Xenopus oocytes
Proc. Natl. Acad. Sci. USA
Differential modulation of rat neuronal nicotinic receptor subtypes by acute application of ethanol
Br. J. Pharmacol.
Mechanism of action of ethanol: initial central nervous system actions
Pharmacol. Rev.
Cellular and molecular neuroscience of alcoholism
Physiol. Rev.
Cloning of a delta opioid receptor by functional expression
Science
Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses
Nat. Genet.
Functional coupling of the delta-, mu-, and kappa-opioid receptors to MAP-kinase and arachidonate release in Chinese hamster ovary cells
J. Neurochem.
Ethanol alters the subcellular localization of delta- and epsilon-protein kinase C in NG108-15 cells
Mol. Pharmacol.
Mutant mice lacking the gamma isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of gamma-aminobutyrate type A receptors
Proc. Natl. Acad. Sci. USA
Differential nociceptive responses in mice lacking the α1B subunit of N-type Ca2+ channels
Neuroreport
Modulation of Ca2+ channels by G-protein beta gamma subunits
Nature
Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKCε
Nat. Neurosci.
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Present address: Division of Psychobiology, Department of Neuroscience, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Sendai, Miyagi 980-8574, Japan.