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Involvement of the Lateral Hypothalamic Peptide Orexin in Morphine Dependence and Withdrawal
Open accessAbstract
The lateral hypothalamus (LH) is implicated in the behavioral actions of drugs of abuse, but the cellular and molecular basis of this role is unclear. Recent identification of neuropeptides localized in LH neurons has allowed for more specific studies of LH function. The LH-specific peptide orexin (hypocretin) has been shown to be important in arousal and sleep regulation. However, orexin cells of the LH project broadly throughout the brain such that orexin may influence other behaviors as well. In this study, we show that orexin neurons, and not nearby LH neurons expressing melanin-concentrating hormone (MCH), have mu-opioid receptors and respond to chronic morphine administration and opiate antagonist-precipitated morphine withdrawal. cAMP response element-mediated transcription is induced in a subset of orexin cells, but not MCH cells, after exposure to chronic morphine or induction of withdrawal. Additionally, c-Fos and the orexin gene itself are induced in orexin cells in the LH during morphine withdrawal. Finally, we show that orexin knock-out mice develop attenuated morphine dependence, as indicated by a less severe antagonist-precipitated withdrawal syndrome. Together, these studies support a role for the orexin system in molecular adaptations to morphine, and demonstrate dramatic differences in molecular responses among different populations of LH neurons.
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Metadata
- Authors
- Georgescu, D., Zachariou, V., Barrot, M., Mieda, M., Willie, J. T., Eisch, A. J., Yanagisawa, M., Nestler, E. J., & DiLeone, R. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-04-15
- Volume
- 23
- Issue
- 8
- Pages
- 3106-3111
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6742290
- OpenAlex
- W2099485542
- Cited by
- 373
- References
- 46
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 16 · 2023: 15 · 2022: 16 · 2021: 12 · 2020: 18 · 2019: 10 · 2018: 20 · 2017: 10 · 2016: 20 · 2015: 15 · 2014: 19 · 2013: 19 · 2012: 27
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- orexin, lateral hypothalamus, morphine dependence, morphine withdrawal, mu-opioid receptor, melanin-concentrating hormone, cAMP response element, c-fos, orexin knockout mice, opioid use disorder, neuronal gene expression
- MeSH terms
- Orexins, Animals, Carrier Proteins, Chronic Disease, Disease Models, Animal, Drug Implants, Gene Expression Regulation, Homozygote, Hypothalamic Hormones, Hypothalamus, Lac Operon, Male, Melanins, Mice, Transgenic, Morphine, Morphine Dependence, Motor Activity, Neurons, Neuropeptides, Pituitary Hormones, Substance Withdrawal Syndrome, Proto-Oncogene Proteins c-fos, Receptors, Opioid, mu, Genes, Reporter, Receptors, Neuropeptide, Mice, Knockout, Response Elements, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Mice, Orexin Receptors
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