Central amygdala circuits mediate hyperalgesia in alcohol-dependent rats
Open accessAbstract
Alcohol withdrawal symptoms contribute to excessive alcohol drinking and relapse in alcohol-dependent individuals. Among these symptoms, alcohol withdrawal promotes hyperalgesia, but the neurological underpinnings of this phenomenon are not known. Chronic alcohol exposure alters cell signaling in the central nucleus of the amygdala (CeA), and the CeA is implicated in mediating alcohol dependence-related behaviors. The CeA projects to the periaqueductal gray (PAG), a region critical for descending pain modulation, and may have a role in alcohol withdrawal hyperalgesia. Here, we tested the roles of (1) CeA projections to PAG, (2) CeA melanocortin signaling, and (3) PAG μ-opioid receptor signaling in mediating thermal nociception and alcohol withdrawal hyperalgesia in male Wistar rats. Our results demonstrate that alcohol dependence reduces GABAergic signaling from CeA terminals onto PAG neurons and alters the CeA melanocortin system, that CeA-PAG projections and CeA melanocortin signaling mediate alcohol withdrawal hyperalgesia, and that μ-opioid receptors in PAG filter CeA effects on thermal nociception. SIGNIFICANCE STATEMENT Hyperalgesia is commonly seen in individuals with alcohol use disorder during periods of withdrawal, but the neurological underpinnings behind this phenomenon are not completely understood. Here, we tested whether alcohol dependence exerts its influence on pain modulation via effects on the limbic system. Using behavioral, optogenetic, electrophysiological, and molecular biological approaches, we demonstrate that central nucleus of the amygdala (CeA) projections to periaqueductal gray mediate thermal hyperalgesia in alcohol-dependent and alcohol-naive rats. Using pharmacological approaches, we show that melanocortin receptor-4 signaling in CeA alters alcohol withdrawal hyperalgesia, but this effect is not mediated directly at synaptic inputs onto periaqueductal gray-projecting CeA neurons. Overall, our findings support a role for limbic influence over the descending pain pathway and identify a potential therapeutic target for treating hyperalgesia in individuals with alcohol use disorder .
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Melanocortin-4 receptor antagonists reduce thermal hyperalgesia in alcohol-dependent rats during withdrawal, mediated by melanocortin-4 receptor signaling in the CeA.
“Intraventricular and intranasal administration of melanocortin-4 receptor antagonists reduced thermal hyperalgesia in alcohol-dependent rats during withdrawal (Roltsch Hellard et al., 2017), and this effect appeared to be mediated by melanocortin-4 receptor signaling in the CeA (Avegno et al., 2018).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Avegno et al., 2018
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Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development
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“Additionally, recent evidence from Avegno et al. implicate the CeA melanocortin system in acute withdrawal, as withdrawal-induced hyperalgesia correlates with reduced MC4R expression in the CeA (Avegno et al., 2018).”
BackgroundKang, S., Li, J., Zuo, W., Chen, P., Gregor, D., Fu, R., Han, X., Bekker, A., & Ye, J.-H. (2019) · Scientific Reports · doi:10.1038/s41598-018-38393-7 · Cited by 47 · see citing works
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- Authors
- Avegno, E. M., Lobell, T. D., Itoga, C. A., Baynes, B. B., Whitaker, A. M., Weera, M. M., Edwards, S., Middleton, J. W., & Gilpin, N. W.
- Affiliations
- Louisiana State University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2018-07-27
- Volume
- 38
- Issue
- 36
- Pages
- 7761-7773
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6125812
- OpenAlex
- W2883247211
- Cited by
- 104
- References
- 49
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 8 · 2023: 13 · 2022: 10 · 2021: 17 · 2020: 24 · 2019: 14 · 2018: 1
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX003451)
- National Institute on Alcohol Abuse and Alcoholism (R00AA020839, R01AA025996, R01AA023305, F32AA025831, T32AA007577)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- central amygdala, periaqueductal gray, melanocortin-4 receptor, mu-opioid receptor, descending pain modulation, thermal nociception, GABAergic neurotransmission, limbic system, alcoholism, descending pain pathway
- MeSH terms
- Alcoholism, Amygdala, Animals, Hot Temperature, Hyperalgesia, Male, Nerve Net, Neural Pathways, Neurons, Periaqueductal Gray, Signal Transduction, Rats, Wistar, Receptors, Opioid, mu, Receptor, Melanocortin, Type 4, Rats
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