title: Brain-Derived Neurotrophic Factor in the Mesolimbic Reward Circuitry Mediates Nociception in Chronic Neuropathic Pain.
abstract: BACKGROUND
  The mesolimbic reward system plays a critical role in modulating nociception; however, its underlying molecular, cellular, and neural circuitry mechanisms remain unknown.
  
  
  METHODS
  Chronic constrictive injury (CCI) of the sciatic nerve was used to model neuropathic pain. Projection-specific in vitro recordings in mouse brain slices and in vivo recordings from anesthetized animals were used to measure firing of dopaminergic neurons in the ventral tegmental area (VTA). The role of VTA-nucleus accumbens (NAc) circuitry in nociceptive regulation was assessed using optogenetic and pharmacological manipulations, and the underlying molecular mechanisms were investigated by Western blotting, enzyme-linked immunosorbent assays, and conditional knockdown techniques.
  
  
  RESULTS
  c-Fos expression in and firing of contralateral VTA-NAc dopaminergic neurons were elevated in CCI mice, and optogenetic inhibition of these neurons reversed CCI-induced thermal hyperalgesia. CCI increased the expression of brain-derived neurotrophic factor (BDNF) protein but not messenger RNA in the contralateral NAc. This increase was reversed by pharmacological inhibition of VTA dopaminergic neuron activity, which induced an antinociceptive effect that was neutralized by injecting exogenous BDNF into the NAc. Moreover, inhibition of BDNF synthesis in the VTA with anisomycin or selective knockdown of BDNF in the VTA-NAc pathway was antinociceptive in CCI mice.
  
  
  CONCLUSIONS
  These results reveal a novel mechanism of nociceptive modulation in the mesolimbic reward circuitry and provide new insight into the neural circuits involved in the processing of nociceptive information.
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China; Department of Pharmacological Sciences, Institute for Systems Biomedicine, New York, New York.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Qian
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Mei-Jun
authors.initials: MJ
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China; Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
authors.forename: He
authors.initials: H
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Guo
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Yang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
authors.forename: Hai-Lei
authors.initials: HL
authors.lastname: Ding
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ja Wook
authors.initials: JW
authors.lastname: Koo
authors.affiliation: Department of Pharmacological Sciences, Institute for Systems Biomedicine, New York, New York.
authors.forename: Ezekiell
authors.initials: E
authors.lastname: Mouzon
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Venetia
authors.initials: V
authors.lastname: Zachariou
authors.affiliation: Department of Pharmacological Sciences, Institute for Systems Biomedicine, New York, New York; Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China; Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Electronic address: caojl0310@aliyun.com.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D007839:Functional Laterality; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects; D009437:Neuralgia / Q000473:pathology* / Q000503:physiopathology*; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012201:Reward
chemical_list: D001552:Benzazepines; D019208:Brain-Derived Neurotrophic Factor; D002316:Cardiotonic Agents; D058786:GABA-B Receptor Agonists; D016760:Proto-Oncogene Proteins c-fos; D011743:Pyrimidines; C082246:ICI D2788; C087873:DK-AH 268; D001418:Baclofen
keywords: BDNF; Dopaminergic neuron; Mesolimbic reward system; Nociception; Nucleus accumbens; Pain; Ventral tegmental area