title: Pain-related depression of the mesolimbic dopamine system in rats: expression, blockade by analgesics, and role of endogenous κ-opioids.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Leitl
authors.affiliation: Behavioral Genetics Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Onvani
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Bowers
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Behavioral Genetics Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Carlezon
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology; D003863:Depression / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007660:Ketoprofen / Q000494:pharmacology; D019344:Lactic Acid / Q000494:pharmacology; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000502:physiology; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000150:complications* / Q000188:drug therapy; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism*; D012653:Self Stimulation; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D044482:Benzeneacetamides; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D019344:Lactic Acid; C051844:norbinaltorphimine; D009271:Naltrexone; D009020:Morphine; D007660:Ketoprofen; C045444:U 69593; D004298:Dopamine