title: Microglia disrupt mesolimbic reward circuitry in chronic pain.
abstract: Chronic pain attenuates midbrain dopamine (DA) transmission, as evidenced by a decrease in opioid-evoked DA release in the ventral striatum, suggesting that the occurrence of chronic pain impairs reward-related behaviors. However, mechanisms by which pain modifies DA transmission remain elusive. Using in vivo microdialysis and microinjection of drugs into the mesolimbic DA system, we demonstrate in mice and rats that microglial activation in the VTA compromises not only opioid-evoked release of DA, but also other DA-stimulating drugs, such as cocaine. Our data show that loss of stimulated extracellular DA is due to impaired chloride homeostasis in midbrain GABAergic interneurons. Treatment with minocycline or interfering with BDNF signaling restored chloride transport within these neurons and recovered DA-dependent reward behavior. Our findings demonstrate that a peripheral nerve injury causes activated microglia within reward circuitry that result in disruption of dopaminergic signaling and reward behavior. These results have broad implications that are not restricted to the problem of pain, but are also relevant to affective disorders associated with disruption of reward circuitry. Because chronic pain causes glial activation in areas of the CNS important for mood and affect, our findings may translate to other disorders, including anxiety and depression, that demonstrate high comorbidity with chronic pain.
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, California 92697, Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095.
authors.forename: Anna M W
authors.identifier: http://orcid.org/0000-0001-7881-8783
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: Institut Universitaire en Santé Mentale de Québec 2601, Chemin de la Canardiere, Québec G1J 2G3, Canada, Department of Psychiatry and Neuroscience, Université Laval, Québec G1V OA6, Canada.
authors.forename: Annie
authors.identifier: http://orcid.org/0000-0001-8065-3359
authors.initials: A
authors.lastname: Castonguay
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Taylor
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095.
authors.forename: Niall P
authors.initials: NP
authors.lastname: Murphy
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Ghogha
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, California 92697.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cook
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada, and.
authors.forename: Lihua
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Psychology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Mary C
authors.identifier: http://orcid.org/0000-0003-2249-4411
authors.initials: MC
authors.lastname: Olmstead
authors.affiliation: Institut Universitaire en Santé Mentale de Québec 2601, Chemin de la Canardiere, Québec G1J 2G3, Canada, Department of Psychiatry and Neuroscience, Université Laval, Québec G1V OA6, Canada.
authors.forename: Yves
authors.identifier: http://orcid.org/0000-0002-5779-9330
authors.initials: Y
authors.lastname: De Koninck
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Evans
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, California 92697, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada, and cmcahill@uci.edu.
authors.forename: Catherine M
authors.identifier: http://orcid.org/0000-0001-7009-9083
authors.initials: CM
authors.lastname: Cahill
mesh_terms: D000818:Animals; D019540:Area Under Curve; D059350:Chronic Pain / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D003042:Cocaine / Q000627:therapeutic use; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008032:Limbic System / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology*; D008911:Minocycline / Q000627:therapeutic use; D009020:Morphine / Q000627:therapeutic use; D009415:Nerve Net / Q000473:pathology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D020426:Sciatic Neuropathy / Q000150:complications; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
chemical_list: D009020:Morphine; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D008911:Minocycline; D003042:Cocaine
keywords: addiction; affective disorder; chronic pain; dopamine; emotion; opioids