title: Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise: A study for specific neural control with Gi-DREADD in mice.
abstract: Exercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia.
  
  
  
  In the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens.
  
  
  
  The chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well.
  
  
  
  Our findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.
authors.affiliation: Department of Anesthesiology, Keio University of Medicine, Tokyo, Japan.|Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Wakaizumi
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Takashige
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Kawabe
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Narita
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University, Fukushima, Japan.|McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kato
authors.affiliation: Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama City, Japan.|Department of Physical Therapy, Osaka Yukioka College of Health Science, Ibaraki City, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Senba
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University, Fukushima, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan n-kuzumaki@hoshi.ac.jp.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.affiliation: Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamanaka
authors.affiliation: Department of Anesthesiology, Keio University of Medicine, Tokyo, Japan morisaki@z8.keio.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morisaki
authors.affiliation: Department of Anesthesiology, Keio University of Medicine, Tokyo, Japan narita@hoshi.ac.jp.|Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.|Life Science Tokyo Advanced Research Center, Tokyo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
mesh_terms: D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005080:Exercise Test; D005081:Exercise Therapy / Q000379:methods*; D006930:Hyperalgesia / Q000209:etiology / Q000534:rehabilitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009437:Neuralgia / Q000473:pathology* / Q000534:rehabilitation*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000503:physiopathology*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D043562:Receptors, G-Protein-Coupled; D012702:Serotonin Antagonists; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; D003024:Clozapine; C079149:clozapine N-oxide; D004298:Dopamine
keywords: Chronic pain; DREADD; brain reward system; exercise-induced hypoalgesia; mesolimbic dopaminergic network; nucleus accumbens; treadmill exercise; ventral tegmental area