Expression of pronociceptin and its receptor is downregulated in the brain of human alcoholics
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Animal studies demonstrated a role of neuropeptide nociceptin (NC) and its receptor (opiate receptor like-1, OPRL1) in ethanol-induced reward; activation of the OPRL1 by natural or synthetic ligands reduced ethanol self-administration and prevented relapse to ethanol drinking. The endogenous NC may function in neuronal circuits involved in reinforcing or conditioning effects of ethanol as a "brake" to limit ethanol intake (Roberto, M., Siggins, G.R. 2006. Nociceptin/orphanin FQ presynaptically decreases GABAergic transmission and blocks the ethanol-induced increase of GABA release in central amygdala. Proc. Natl. Acad. Sci. USA 103. 9715-9720), whereas repeated ethanol intake may downregulate the endogenous NC/OPRL1 system resulting in activation of ethanol consumption. To address this hypothesis, we evaluated whether expression of the pronociceptin (PNOC) and OPRL1 genes is altered in human alcoholics. mRNAs transcribed from these genes were analyzed by quantitative RT-PCR in the prefrontal and orbitofrontal cortices, central amygdala and hippocampal dentate gyrus, structures controlling alcohol consumption. Reduction in PNOC mRNA (1.7-fold) was found in the hippocampus of alcoholics, whereas OPRL1 mRNA levels were decreased (1.4-fold) in the central amygdala. No changes in expression of these genes in other brain areas analyzed were evident. We hypothesise that chronic ethanol intake downregulates PNOC and OPRL1 gene expression in the hippocampus and amygdala, respectively. The findings may be also interpreted as inherited molecular differences between alcoholics and controls. The PNOC/OPRL1 downregulation may underlie impairment of cognitive control over alcohol seeking in alcoholics. Stimulation of the OPRL1 receptors with synthetic agonists may increase threshold for activation of ethanol-related behaviour by environmental cues, and thus may reduce cue- or stress-primed relapse to ethanol consumption.
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In postmortem brains of humans with AUD, nociceptin mRNA decreases in the amygdala.
“In postmortem brains of humans with AUD, nociceptin mRNA decreased in the amygdala (Kuzmin et al., 2009).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Kuzmin et al., 2009
The Results (section 2; page not provided) report lower pronociceptin (PNOC) mRNA in the hippocampus, with no evident PNOC difference in the other regions analyzed, including the central amygdala. The mRNA found to be lower in the central amygdala was for the nociceptin receptor (OPRL1), not nociceptin. (LLM, conf=0.91)
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Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development
Koob, G. F. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000083 · Cited by 337 · see citing works
- Authors
- Kuzmin, A., Bazov, I., Sheedy, D., Garrick, T., Harper, C., & Bakalkin, G.
- Affiliations
- Uppsala University (SE)
- The University of Sydney (AU)
- Corresponding author
- Bakalkin, Georgy
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 1305
- Pages
- S80-S85
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC3391552
- OpenAlex
- W2019037474
- Cited by
- 40
- References
- 33
- Citations by year
- 2026: 2 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 3 · 2012: 3
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vetenskapsrådet
- Systembolaget Aktiebolag
- National Health and Medical Research Council
- National Medical Research Council
- National Institute on Alcohol Abuse and Alcoholism (R24AA012725, R28AA012725)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- nociceptin, opioid receptor-like 1, alcoholism, gene downregulation, hippocampus, central amygdala, prefrontal cortex, orbitofrontal cortex, chronic alcohol consumption, alcohol relapse, ethanol self-administration, GABAergic neurotransmission
- MeSH terms
- Nociceptin Receptor, Alcoholism, Brain, Humans, Male, Middle Aged, Protein Precursors, Receptors, Opioid, RNA, Messenger, Smoking, Reverse Transcriptase Polymerase Chain Reaction, White People
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