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 be engaged in negative emotional states associated with chronic pain.
“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
The Discussion reports that dynorphin-containing neurons and kappa opioid receptor activity drive negative affect associated with inflammatory pain. This supports engagement of the system in pain-related negative emotional states, but the study’s findings are specifically in rodent models of inflammatory pain, not chronic pain generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredLocal infusion of nor-BNI into the ventral NAc shell blocks conditioned place aversion and lower motivation to self-administer sucrose produced by inflammation.
“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
The Results section on KORs and pain-induced negative affect reports that local norBNI prevented or reversed the inflammation-induced decrease in motivation to self-administer sucrose. The Results section on dynorphin-containing neurons reports that 4 μg of norBNI in the ventral NAc shell blocked real-time place aversion during inflammatory pain. That aversion was induced by photo-stimulation, not shown to be conditioned place aversion produced by inflammation; 2 μg did not prevent it after inflammation. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn chronic inflammatory pain, dynorphin expression increases in dynorphin-containing neurons in a discrete subregion of the NAc shell through a disinhibition mechanism, and pain increases k-opioid receptor function.
“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
Dynorphin-containing neurons and k-opioid receptor activity in the NAc shell are necessary and sufficient to drive pain-induced negative affective states.
“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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- 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 › 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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