Pain-related depression of the mesolimbic dopamine system in rats: expression, blockade by analgesics, and role of endogenous κ-opioids
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Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This study tested the hypothesis that pain-related behavioral depression is mediated by activation of endogenous κ-opioid systems and subsequent depression of mesolimbic dopamine release. Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self-stimulation (ICSS)) or with cannulae for microdialysis measures of nucleus accumbens dopamine (NAc DA). Changes in ICSS and NAc DA were examined after treatment with a visceral noxious stimulus (intraperitoneal injection of dilute lactic acid) or an exogenous κ-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the μ-opioid agonist morphine) or by the κ-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and κ-opioid receptors (KORs) in mesocorticolimbic brain regions. Both acid and U69593 depressed ICSS and extracellular levels of NAc DA. Pain-related acid effects were blocked by ketoprofen and morphine but not by norBNI. The U69593 effects were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. Acid did not significantly alter PDYN or KOR in NAc, but it produced a delayed increase in PDYN in prefrontal cortex. These results support a key role for the mesolimbic DA system, but a more nuanced role for endogenous κ-opioid systems, in mediating acute pain-related behavioral depression in rats.
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nor-BNI fails to block lactic acid-induced elevations of brain reward thresholds and decrease in NAc dopamine in rats.
“Moreover, the k-opioid receptor antagonist nor-BNI failed to block lactic acidinduced elevations of brain reward thresholds and the decrease in NAc dopamine in rats (Leitl et al., 2014).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Leitl et al., 2014
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References 52 · Cited by 87
- Authors
- Leitl, M. D., Onvani, S., Bowers, M. S., Cheng, K., Rice, K. C., Carlezon, W. A., Banks, M. L., & Negus, S. S.
- Affiliations
- Virginia Commonwealth University (US)
- Harvard University (US)
- National Institutes of Health (US)
- Corresponding author
- Negus, S Stevens
- Venue
- Neuropsychopharmacology
- Published
- 2013-09-06
- Volume
- 39
- Issue
- 3
- Pages
- 614-624
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3895239
- OpenAlex
- W1966351569
- Cited by
- 87
- References
- 52
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 9 · 2020: 7 · 2019: 13 · 2018: 6 · 2017: 3 · 2016: 12 · 2015: 11 · 2014: 8 · 2013: 1
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000058)
- National Institute on Drug Abuse (T32DA007027)
- National Institute of Neurological Disorders and Stroke (R01NS070715)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- pain-related depression, mesolimbic dopamine system, kappa opioid receptor, visceral pain, lactic acid, intraperitoneal injection, intracranial self-stimulation, nucleus accumbens dopamine, ketoprofen, morphine, nor-binaltorphimine, prodynorphin, prefrontal cortex
- MeSH terms
- Analgesics, Opioid, Animals, Depression, Disease Models, Animal, Dopamine, Gene Expression Regulation, Ketoprofen, Male, Medial Forebrain Bundle, Morphine, Naltrexone, Narcotic Antagonists, Nucleus Accumbens, Pain, Pyrrolidines, Self Stimulation, Time Factors, Rats, Sprague-Dawley, Receptors, Opioid, kappa, Lactic Acid, Benzeneacetamides, Rats
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