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Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus Accumbens Kappa Opioid System
Open accessAbstract
Negative affective states affect quality of life for patients suffering from pain. These maladaptive emotional states can lead to involuntary opioid overdose and many neuropsychiatric comorbidities. Uncovering the mechanisms responsible for pain-induced negative affect is critical in addressing these comorbid outcomes. The nucleus accumbens (NAc) shell, which integrates the aversive and rewarding valence of stimuli, exhibits plastic adaptations in the presence of pain. In discrete regions of the NAc, activation of the kappa opioid receptor (KOR) decreases the reinforcing properties of rewards and induces aversive behaviors. Using complementary techniques, we report that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is necessary and sufficient to drive pain-induced negative affect. Taken together, our results provide evidence that pain-induced adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention that could circumvent pain-induced affective disorders. VIDEO ABSTRACT.
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“The dynorphin/k-opioid receptor system may also be engaged in negative emotional states that are associated with chronic pain (Cahill et al., 2014;Massaly et al., 2016Massaly et al., , 2019)).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Massaly et al., 2019
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“The local infusion of microgram amounts of the k-opioid receptor antagonist nor-BNI into the ventral NAc shell blocked conditioned place aversion and the lower motivation to self-administer sucrose that was produced by inflammation (Massaly et al., 2019).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Massaly et al., 2019
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“Indeed, in a study of chronic inflammatory pain that was induced by a hindpaw injection of Complete Freund's Adjuvant, dynorphin expression increased in dynorphin-containing neurons in a discrete subregion of the NAc shell through a disinhibition mechanism, and pain increased k-opioid receptor function (Massaly et al., 2019).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Massaly et al., 2019
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“Even more compelling, using a series of pharmacological, optogenetic, and chemogenetic approaches, the authors showed that both dynorphin-containing neurons and k-opioid receptor activity in the NAc shell were necessary and sufficient to drive pain-induced negative affective states (Massaly et al., 2019).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Massaly et al., 2019
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Neurons containing hypocretin (orexin) project to multiple neuronal systems
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A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor
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CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety
McCall, J. G., Al-Hasani, R., Siuda, E. R., Hong, D. Y., Norris, A. J., Ford, C. P., & Bruchas, M. R. (2015) · Neuron · doi:10.1016/j.neuron.2015.07.002 · Cited by 666
Self-citationAn excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger
Krashes, M. J., Shah, B. P., Madara, J. C., Olson, D. P., Strochlic, D. E., Garfield, A. S., Vong, L., Pei, H., Watabe-Uchida, M., Uchida, N., et al. (2014) · Nature · doi:10.1038/nature12956 · Cited by 603
The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System
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Self-citationThe dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors
Bruchas, M. R., Land, B. B., & Chavkin, C. (2010) · Brain Research · doi:10.1016/j.brainres.2009.08.062 · Cited by 544
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Neurobiology of opioid addiction: Opponent process, hyperkatifeia, and negative reinforcement
Koob, G. F. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.05.023 · Cited by 477
Cellular Circuits in the Brain and Their Modulation in Acute and Chronic Pain
Kuner, R., & Kuner, T. (2020) · Physiological Reviews · doi:10.1152/physrev.00040.2019 · Cited by 371
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Castro, D. C., & Bruchas, M. R. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.003 · Cited by 306
Self-citationBrain circuits for pain and its treatment
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Metadata
- Authors
- Massaly, N., Copits, B. A., Wilson-Poe, A. R., Hipólito, L., Markovic, T., Yoon, H. J., Liu, S., Walicki, M. C., Bhatti, D. L., Sirohi, S., Klaas, A., Walker, B. M., Neve, R., Cahill, C. M., Shoghi, K. I., Gereau, R. W., McCall, J. G., Al-Hasani, R., Bruchas, M. R., & Morón, J. A.
- Affiliations
- Washington University in St. Louis (US)
- University of California, Los Angeles (US)
- University of Health Sciences and Pharmacy (US)
- Washington State University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Bruchas, Michael R.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 102
- Issue
- 3
- Pages
- 564-573.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6509001
- OpenAlex
- W2922000881
- Cited by
- 200
- References
- 45
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 21 · 2023: 16 · 2022: 27 · 2021: 49 · 2020: 28 · 2019: 12
- FWCI
- 13.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (DA041781, DA042581, DA042499, DA041883, DA045463)
- Brain and Behavior Research Foundation (DA033396, DA037152, R01-NS106953, AA020394, K99/R00-DA038725, K99-DA041467)
- Philippe Foundation
- Mallinckrodt Institute of Radiology at Washington University (16-014)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- nucleus accumbens shell, kappa opioid receptor, opioid overdose, aversive behavior, reward processing
- MeSH terms
- Affect, Animals, Dynorphins, Inflammation, Neural Inhibition, Neuronal Plasticity, Neurons, Nucleus Accumbens, Pain, Receptors, Opioid, kappa, Mood Disorders, Mice, Rats
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