PMID- 28390647 OWN - NLM STAT- MEDLINE DCOM- 20180521 LR - 20220321 IS - 1873-2402 (Electronic) IS - 0006-3223 (Print) IS - 0006-3223 (Linking) VI - 82 IP - 8 DP - 2017 Oct 15 TI - Brain-Derived Neurotrophic Factor in the Mesolimbic Reward Circuitry Mediates Nociception in Chronic Neuropathic Pain. PG - 608-618 LID - S0006-3223(17)31353-7 [pii] LID - 10.1016/j.biopsych.2017.02.1180 [doi] AB - 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. CI - Copyright (c) 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. FAU - Zhang, Hongxing AU - Zhang H AD - 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. FAU - Qian, Yi-Ling AU - Qian YL AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Li, Chen AU - Li C AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Liu, Di AU - Liu D AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Wang, Lei AU - Wang L AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Wang, Xiao-Yi AU - Wang XY AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Liu, Mei-Jun AU - Liu MJ AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Liu, He AU - Liu H AD - 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. FAU - Zhang, Song AU - Zhang S AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Guo, Xiao-Yun AU - Guo XY AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Yang, Jun-Xia AU - Yang JX AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Ding, Hai-Lei AU - Ding HL AD - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China. FAU - Koo, Ja Wook AU - Koo JW AD - Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Mouzon, Ezekiell AU - Mouzon E AD - Department of Pharmacological Sciences, Institute for Systems Biomedicine, New York, New York. FAU - Deisseroth, Karl AU - Deisseroth K AD - Department of Bioengineering, Stanford University, Stanford, California. FAU - Nestler, Eric J AU - Nestler EJ AD - Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Zachariou, Venetia AU - Zachariou V AD - Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Han, Ming-Hu AU - Han MH AD - 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. FAU - Cao, Jun-Li AU - Cao JL AD - 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. LA - eng GR - R01 AA022445/AA/NIAAA NIH HHS/United States GR - P01 DA008227/DA/NIDA NIH HHS/United States GR - R21 MH112081/MH/NIMH NIH HHS/United States GR - R01 MH051399/MH/NIMH NIH HHS/United States GR - R01 MH092306/MH/NIMH NIH HHS/United States GR - P50 MH096890/MH/NIMH NIH HHS/United States GR - R01 DA014133/DA/NIDA NIH HHS/United States PT - Journal Article DEP - 20170301 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 0 (Benzazepines) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cardiotonic Agents) RN - 0 (GABA-B Receptor Agonists) RN - 0 (Proto-Oncogene Proteins c-fos) RN - 0 (Pyrimidines) RN - 133059-99-1 (ICI D2788) RN - 155233-34-4 (DK-AH 268) RN - H789N3FKE8 (Baclofen) SB - IM CIN - Biol Psychiatry. 2017 Oct 15;82(8):e61-e63. PMID: 28935098 MH - Animals MH - Baclofen/pharmacology MH - Benzazepines/pharmacology MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Cardiotonic Agents/pharmacology MH - Disease Models, Animal MH - Dopaminergic Neurons/metabolism/pathology MH - Functional Laterality MH - GABA-B Receptor Agonists/pharmacology MH - Limbic System/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neural Inhibition/drug effects MH - Neuralgia/*pathology/*physiopathology MH - Nociception/drug effects/*physiology MH - Pain Threshold/physiology MH - Proto-Oncogene Proteins c-fos/metabolism MH - Pyrimidines/pharmacology MH - *Reward PMC - PMC5788809 MID - NIHMS866216 OTO - NOTNLM OT - BDNF OT - Dopaminergic neuron OT - Mesolimbic reward system OT - Nociception OT - Nucleus accumbens OT - Pain OT - Ventral tegmental area COIS- FINANCIAL DISCLOSURES All authors report no biomedical financial interests or potential conflicts of interest. EDAT- 2017/04/10 06:00 MHDA- 2018/05/22 06:00 PMCR- 2018/10/15 CRDT- 2017/04/10 06:00 PHST- 2016/08/31 00:00 [received] PHST- 2017/01/18 00:00 [revised] PHST- 2017/02/21 00:00 [accepted] PHST- 2017/04/10 06:00 [pubmed] PHST- 2018/05/22 06:00 [medline] PHST- 2017/04/10 06:00 [entrez] PHST- 2018/10/15 00:00 [pmc-release] AID - S0006-3223(17)31353-7 [pii] AID - 10.1016/j.biopsych.2017.02.1180 [doi] PST - ppublish SO - Biol Psychiatry. 2017 Oct 15;82(8):608-618. doi: 10.1016/j.biopsych.2017.02.1180. Epub 2017 Mar 1.