Exploring the opioid system by gene knockout
Abstract
The endogenous opioid system consists of three opioid peptide precursor genes encoding enkephalins (preproenkephalin, Penk), dynorphins (preprodynorphin, Pdyn) and beta-endorphin (betaend), proopiomelanocortin (POMC) and three receptor genes encoding mu-opiod receptor (MOR), delta-opiod receptor (DOR) and kappa-opiod receptor (KOR). In the past years, all six genes have been inactivated in mice by homologous recombination. The analysis of spontaneous behavior in mutant mice has demonstrated significant and distinct roles of each gene in modulating locomotion, pain perception and emotional behaviors. The observation of opposing phenotypes of MOR- and DOR-deficient mice in several behaviors highlights unexpected roles for DOR to be further explored genetically and using more specific delta compounds. The analysis of responses of mutant mice to exogenous opiates has definitely clarified the essential role of MOR in both morphine analgesia and addiction, and demonstrated that DOR and KOR remain promising targets for pain treatment. These studies also show that prototypic DOR agonists partially require MOR for their biological activity and provide some support for the postulated mu-delta interactions in vivo. Finally, data confirm and define a role for several genes of the opioid system in responses to other drugs of abuse, and the triple opioid receptor knockout mutant allows exploring non-classical opioid pharmacology. In summary, the study of null mutant mice has extended our previous knowledge of the opioid system by identifying the molecular players in opioid pharmacology and physiology. Future studies should involve parallel behavioral analysis of mice lacking receptors and peptides and will benefit from more sophisticated gene targeting approaches, including site-directed and anatomically-restricted mutations.
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Behavioral differences in Oprm1 mutant mice compared with wild-type mice showed that pain and emotional-like and reward-related behaviors correlated predominantly with alterations within reward/aversion pathways.
“Behavioral differences in Oprm1 mutant mice compared with wild-type mice showed that pain and emotional-like and rewardrelated behaviors correlated predominantly with alterations within reward/aversion pathways (Kieffer and Gaveriaux-Ruff, 2002).”
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- Authors
- Kieffer, B. L., & Gavériaux-Ruff, C.
- Affiliations
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Corresponding author
- Kieffer, Brigitte L
- ORCID
- Kieffer, Brigitte L
- Venue
- Progress in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2002-04
- Volume
- 66
- Issue
- 5
- Pages
- 285-306
- ISSN
- 0301-0082 (ISSN-L)
- OpenAlex
- W2086139880
- Cited by
- 620
- References
- 1
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 15 · 2021: 19 · 2020: 15 · 2019: 19 · 2018: 17 · 2017: 16 · 2016: 23 · 2015: 23 · 2014: 26 · 2013: 33 · 2012: 28
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Progress in Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- endogenous opioid system, mu-opioid receptor, delta opioid receptor, kappa opioid receptor, preproenkephalin, preprodynorphin, beta-endorphin, proopiomelanocortin, locomotion, pain perception, emotional behavior, morphine analgesia, opioid use disorder, opioid pharmacology
- MeSH terms
- Animals, Brain Chemistry, Receptors, Opioid, Mice, Knockout, Opioid Peptides, Mice
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