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J Neurosci. 2019 May 22;39(21):4162-4178. doi: 10.1523/JNEUROSCI.0274-19.2019. Epub 2019 Mar 12.

Kappa Opioid Receptors Drive a Tonic Aversive Component of Chronic Pain.

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Department of Pharmacology, University of California Irvine, School of Medicine, Irvine, California 92697.
Shirley and Stefan Hatos Center for Neuropharmacology.
Jane & Terry Semel Institute for Neuroscience and Human Behavior.
Department of Psychiatry and Biobehavioral Sciences.
Departments of Comparative Biology and Experimental Medicine.
Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Department of Pharmacology, University of the Basque Country UPV/EHU and Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Leioa E-48940, Basque Country, Spain.
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095.
Department of Psychology, Queen's University, Kingston, Ontario, Canada, K7L 3N6.
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada, T6G 2R3.
Research Triangle Institute, Research Triangle Park, North Carolina 27709, and.
Department of Pharmacology and Toxicology, Jacobs School of Medicine, University at Buffalo, Buffalo, New York 14203.
Shirley and Stefan Hatos Center for Neuropharmacology,


Pain is a multidimensional experience and negative affect, or how much the pain is "bothersome", significantly impacts the sufferers' quality of life. It is well established that the κ opioid system contributes to depressive and dysphoric states, but whether this system contributes to the negative affect precipitated by the occurrence of chronic pain remains tenuous. Using a model of persistent pain, we show by quantitative real-time-PCR, florescence in situ hybridization, Western blotting and GTPgS autoradiography an upregulation of expression and the function of κ opioid receptors (KORs) and its endogenous ligand dynorphin in the mesolimbic circuitry in animals with chronic pain compared with surgical controls. Using in vivo microdialysis and microinjection of drugs into the mesolimbic dopamine system, we demonstrate that inhibiting KORs reinstates evoked dopamine release and reward-related behaviors in chronic pain animals. Chronic pain enhanced KOR agonist-induced place aversion in a sex-dependent manner. Using various place preference paradigms, we show that activation of KORs drives pain aversive states in male but not female mice. However, KOR antagonist treatment was effective in alleviating anxiogenic and depressive affective-like behaviors in both sexes. Finally, ablation of KORs from dopamine neurons using AAV-TH-cre in KORloxP mice prevented pain-induced aversive states as measured by place aversion assays. Our results strongly support the use of KOR antagonists as therapeutic adjuvants to alleviate the emotional, tonic-aversive component of chronic pain, which is argued to be the most significant component of the pain experience that impacts patients' quality of life.SIGNIFICANCE STATEMENT We show that KORs are sufficient to drive the tonic-aversive component of chronic pain; the emotional component of pain that is argued to significantly impact a patient's quality of life. The impact of our study is broadly relevant to affective disorders associated with disruption of reward circuitry and thus likely contributes to many of the devastating sequelae of chronic pain, including the poor response to treatment of many patients, debilitating affective disorders (other disorders including anxiety and depression that demonstrate high comorbidity with chronic pain) and substance abuse. Indeed, coexisting psychopathology increases pain intensity, pain-related disability and effectiveness of treatments (Jamison and Edwards, 2013).


aversion; chronic pain; dopamine; emotion; negative affect; opiate

[Available on 2019-11-22]

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