Elsevier

Neuroscience Research

Volume 44, Issue 2, October 2002, Pages 121-131
Neuroscience Research

Update article
Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys?

https://doi.org/10.1016/S0168-0102(02)00094-9Get rights and content

Abstract

Opioids and ethanol have been used since ancient times for pain relief. Opioid signaling is mediated by various effectors, including G protein-activated inwardly rectifying potassium (GIRK) channels, adenylyl cyclases, voltage-dependent calcium channels, phospholipase Cβ(PLCβ), and mitogen-activated protein kinases, although it has been unclear which effector mediates the analgesic effects of opioids. Ethanol induces a variety of physiological phenomena via various proteins, including GIRK channels rather than via membrane lipids. GIRK channel activation by either G proteins or ethanol is impaired in weaver mutant mice. The mutant mice may therefore serve as a useful animal model for studying the role of GIRK channels in vivo. Reduced analgesia by using either opioids or ethanol in weaver mutant mice suggests that GIRK channels are important effectors in both opioid- and ethanol-induced analgesia. This hypothesis is supported by similar findings in GIRK2 knockout mice. Among the various effectors coupled with opioid receptors and various targets of ethanol, GIRK channels are the only molecules whose involvement in opioid- and ethanol-induced analgesia has been demonstrated in vivo. The GIRK channel is potentially one of the key molecules in furthering the understanding of the pain control system and in developing advanced analgesics with fewer adverse effects.

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

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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.

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