Cited by 96Pain Mechanisms and TreatmentsNeuropeptides and Animal PhysiologyPain Management and Placebo Effect

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Lateralized kappa opioid receptor signaling from the amygdala central nucleus promotes stress-induced functional pain

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Nation, Kelsey M., De Felice, Milena, Hernandez, Pablo I., Dodick, David W., Neugebauer, Volker, Navratilova, Edita, Porreca, Frank·2018·Pain

DOI 10.1097/j.pain.0000000000001167PMC PMC5916844

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Abstract

The response of diffuse noxious inhibitory controls (DNIC) is often decreased, or lost, in stress-related functional pain syndromes. Because the dynorphin/kappa opioid receptor (KOR) pathway is activated by stress, we determined its role in DNIC using a model of stress-induced functional pain. Male, Sprague-Dawley rats were primed for 7 days with systemic morphine resulting in opioid-induced hyperalgesia. Fourteen days after priming, when hyperalgesia was resolved, rats were exposed to environmental stress and DNIC was evaluated by measuring hind paw response threshold to noxious pressure (test stimulus) after capsaicin injection in the forepaw (conditioning stimulus). Morphine priming without stress did not alter DNIC. However, stress produced a loss of DNIC in morphine-primed rats in both hind paws that was abolished by systemic administration of the KOR antagonist, nor-binaltorphimine (nor-BNI). Microinjection of nor-BNI into the right, but not left, central nucleus of the amygdala (CeA) prevented the loss of DNIC in morphine-primed rats. Diffuse noxious inhibitory controls were not modulated by bilateral nor-BNI in the rostral ventromedial medulla. Stress increased dynorphin content in both the left and right CeA of primed rats, reaching significance only in the right CeA; no change was observed in the rostral ventromedial medulla or hypothalamus. Although morphine priming alone is not sufficient to influence DNIC, it establishes a state of latent sensitization that amplifies the consequences of stress. After priming, stress-induced dynorphin/KOR signaling from the right CeA inhibits DNIC in both hind paws, likely reflecting enhanced descending facilitation that masks descending inhibition. Kappa opioid receptor antagonists may provide a new therapeutic strategy for stress-related functional pain disorders.

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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

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Authors: Nation, K. M., De Felice, M., Hernandez, P. I., Dodick, D. W., Neugebauer, V., Navratilova, E., & Porreca, F.
Affiliations: University of Arizona (US)
Department of Pharmacology, University of Arizona, Tucson, AZ, USA. Dr. De Felice is now with the School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom
Mayo Clinic in Arizona (US)
Texas Tech University Health Sciences Center (US)
Corresponding author: Porreca, Frank
ORCID: Nation, Kelsey M.
Dodick, David W.
Neugebauer, Volker
Navratilova, Edita
Porreca, Frank
Venue: Pain
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2018-01-23
Volume: 159
Issue: 5
Pages: 919-928
ISSN: 0304-3959 (ISSN-L)
1872-6623
DOI: 10.1097/j.pain.0000000000001167
PMC: PMC5916844
OpenAlex: W2801864057
Cited by: 96
References: 93
Citations by year: 2026: 5 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 15 · 2021: 18 · 2020: 17 · 2019: 10 · 2018: 7
FWCI: 8.92
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Pain (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (R25HL108837)
National Institute on Drug Abuse (R01DA041809)
National Cancer Institute (P30CA023074)
National Institute of Neurological Disorders and Stroke (UH2NS093030, R01NS038261)
Topics: Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
Keywords: kappa opioid receptor, dynorphin, diffuse noxious inhibitory control, central amygdala, opioid-induced hyperalgesia, nor-binaltorphimine, descending facilitation, descending inhibition, laterality, rostral ventromedial medulla
MeSH terms: Analgesics, Opioid, Animals, Capsaicin, Dynorphins, Hypothalamus, Male, Medulla Oblongata, Morphine, Naltrexone, Narcotic Antagonists, Pain, Stress, Physiological, Rats, Sprague-Dawley, Receptors, Opioid, kappa, Rats, Central Amygdaloid Nucleus

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Lateralized kappa opioid receptor signaling from the amygdala central nucleus promotes stress-induced functional pain

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