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Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action
Open accessAbstract
Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-binding regulatory protein-linked μ, δ, and κ opioid receptors. One major effector for these receptors is adenylyl cyclase, which is inhibited upon receptor activation. However, little is known about which of the ten known forms of adenylyl cyclase are involved in mediating opioid actions. Here we show that all of the major behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective μ or δ opioid receptor agonists are lost in AC5 −/− mice, whereas the behavioral effects of selective κ opioid receptor agonists are unaffected. These behavioral data are consistent with the observation that the ability of a μ or δ opioid receptor agonist to suppress adenylyl cyclase activity was absent in striatum of AC5 −/− mice. Together, these results establish AC5 as an important component of μ and δ opioid receptor signal transduction mechanisms in vivo and provide further support for the importance of the cAMP pathway as a critical mediator of opioid action.
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“genetic knockout of adenylyl cyclase type 5 in mice prevents the reward response to opioids such as morphine [81].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [81]
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Metadata
- Authors
- Kim, K.-S., Lee, K.-W., Lee, K.-W., Im, J.-Y., Yoo, J. Y., Kim, S.-W., Lee, J.-K., Nestler, E. J., & Han, P.-L.
- Affiliations
- Ewha Womans University (KR)
- Inha University (KR)
- The University of Texas Southwestern Medical Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-02-28
- Volume
- 103
- Issue
- 10
- Pages
- 3908-3913
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2139496188
- Cited by
- 123
- References
- 51
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 10 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 8 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 13
- FWCI
- 4.30
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- adenylyl cyclase type 5, morphine, opioid receptors, mu-opioid receptor, delta opioid receptor, kappa opioid receptor, striatum, cAMP signaling, opioid tolerance, opioid reward, opioid use disorder, opioid withdrawal, analgesia, locomotor activation
- MeSH terms
- Adenylyl Cyclases, Animals, Behavior, Animal, Conditioning, Psychological, Corpus Striatum, Isoenzymes, Mice, Inbred C57BL, Morphine, Motor Activity, Pain Measurement, Receptors, Opioid, Substance Withdrawal Syndrome, Signal Transduction, Receptors, Opioid, mu, Receptors, Opioid, delta, Mice, Knockout, Mice
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