Opioids: first lessons from knockout mice

doi:10.1016/S0165-6147(98)01279-6

Trends in Pharmacological Sciences

Volume 20, Issue 1, 1 January 1999, Pages 19-26

https://doi.org/10.1016/S0165-6147(98)01279-6 Get rights and content

Abstract

Opioid receptors of the μ-, δ- and κ-subtypes mediate the potent analgesic and addictive actions of opioid drugs. They also regulate responses to pain, stress and emotions when activated by endogenous opioid peptides. Recently, mice lacking opioid receptors or opioid peptides have been produced by gene targeting, providing molecular tools to study opioid function in vivo. Observations on mutant mice have shed new light on the mode of action of opioids, opioid receptor heterogeneity and interactions, and the involvement of each component of the opioid system in mouse physiology. In this article, Brigitte L. Kieffer reviews the first reported studies and discusses their therapeutic implications.

Section snippets

The mode of action of opioid drugs: which molecular target?

Morphine is the prototypic opioid. In contrast to many synthetic opioids that have been developed in the past 20 years, morphine is an opioid compound with low receptor selectivity. Binding studies performed on rodent brain membranes22, 24 or recombinant receptor preparations²³ have shown that morphine exhibits a preference for μ-receptors, with K_i values in the nanomolar range, but also binds to δ- and κ-receptors with submicromolar affinities. This two-order-of magnitude selectivity factor

Opioid receptor heterogeneity and cross-talk: what do knockout mice tell us?

A first level of complexity in opioid receptor pharmacology is the postulated existence of functional interactions between opioid receptors36, 37. A second consideration is the pharmacological diversity of opioid receptor sites37, 38, 39, 40, which exceeds that of the opioid receptor gene family. Although little has been done so far, the use of receptor-deficient mice has provided some insights into the molecular aspects of these highly debated issues.

The cross-talk between μ- and δ-receptors

The role of different components of the opioid system in mouse physiology

In addition to MOR-, DOR- and KOR-deficient mice, mutant mice lacking preproenkephalin⁴⁶ and β-endorphin⁴⁷ have been produced. Although the inactivation of all components of the opioid system has not been completed (prodynorphin-deficient mice have not been reported yet), the successful generation of homozygous mutant mice suggests that the absence of a single component of the opioid system is not lethal under home-cage conditions. Furthermore, the adult mice are fertile and display no marked

Concluding remarks

Mice that lack opioid receptors have proven extremely useful to determine the molecular mode of action of a number of prototypic opioids and represent invaluable tools in drug discovery programmes for the development of novel therapeutic opioids. These mutant mice allow the clarification of some aspects of opioid receptor heterogeneity at the molecular level. Their use for the study of opioid receptor cross-talk is at an early stage, and the issue of functional interactions of the opioid system

Acknowledgements

I am grateful to D. Massotte and I. Kitchen for critical review of the manuscript. I thankfully acknowledge Dr F. Pattus and Prof. P. Chambon for their constant support, as well as K. Befort, D. Filliol, C. Gavériaux-Ruff, H. Matthes and F. Simonin for excellent interactions and work.

Glossary

Chemical names

CI977:: (5R)-(5α,7α,8β-(−)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]-4-benzofuranacetamide monohydrochloride)
U50488H:: (±)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzenacetamide

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Trends in Pharmacological Sciences

ReviewOpioids: first lessons from knockout mice

Abstract

Section snippets

The mode of action of opioid drugs: which molecular target?

Opioid receptor heterogeneity and cross-talk: what do knockout mice tell us?

The role of different components of the opioid system in mouse physiology

Concluding remarks

Acknowledgements

Glossary

Chemical names

Cell. Mol. Neurobiol.

FASEB J.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Mol. Brain Res.

Soc. Neurosci. Abstr.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Life Sci.

Soc. Neurosci. Abstr.

Br. Med. Bull.

Trends Pharmacol. Sci.

Drug Safety

Semin. Neurosci.

Science

Science

Annu. Rev. Neurosci.

Pharmacol. Ther.

Peptides

Am. Rev. Respir. Dis.

Pharmacol. Rev.

Review
Opioids: first lessons from knockout mice