Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

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 mesolimbi...

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Veröffentlicht in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2014-02, Vol.39 (3), p.614-624
Hauptverfasser: LEITL, Michael D, ONVANI, Sara, BOWERS, M. Scott, KEJUN CHENG, RICE, Kenner C, CARLEZON, William A, BANKS, Matthew L, NEGUS, S. Stevens
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container_title Neuropsychopharmacology (New York, N.Y.)
container_volume 39
creator LEITL, Michael D
ONVANI, Sara
BOWERS, M. Scott
KEJUN CHENG
RICE, Kenner C
CARLEZON, William A
BANKS, Matthew L
NEGUS, S. Stevens
description 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.
doi_str_mv 10.1038/npp.2013.236
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source MEDLINE; SpringerLink Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects Adult and adolescent clinical studies
Analgesics
Analgesics, Opioid - pharmacology
Animals
Benzeneacetamides - pharmacology
Biological and medical sciences
Depression
Depression - etiology
Depression - metabolism
Depression - pathology
Disease Models, Animal
Dopamine - metabolism
Gene Expression Regulation - drug effects
Ketoprofen - pharmacology
Lactic Acid - pharmacology
Male
Medial Forebrain Bundle - drug effects
Medial Forebrain Bundle - physiology
Medical sciences
Mood disorders
Morphine - pharmacology
Naltrexone - analogs & derivatives
Naltrexone - pharmacology
Narcotic Antagonists - pharmacology
Nucleus Accumbens - drug effects
Nucleus Accumbens - metabolism
Original
Pain - complications
Pain - drug therapy
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Pyrrolidines - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Opioid, kappa - genetics
Receptors, Opioid, kappa - metabolism
Self Stimulation
Time Factors
title Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids
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