Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise: A study for specific neural control with Gi-DREADD in mice

Kenta Wakaizumi, Takashige Kondo, Yusuke Hamada, Michiko Narita, Rui Kawabe, Hiroki Narita, Moe Watanabe, Shigeki Kato, Emiko Senba, Kazuto Kobayashi, Naoko Kuzumaki, Akihiro Yamanaka, Hiroshi Morisaki, Minoru Narita

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
JournalMolecular Pain
Volume12
DOIs
Publication statusPublished - 2016 Nov 1

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Ventral Tegmental Area
Neuralgia
Nucleus Accumbens
Reward
Emotions
Pain
Pain Threshold
Pleasure
Nociception
Dopaminergic Neurons
Sciatic Nerve
G-Protein-Coupled Receptors
Chronic Pain
Transgenic Mice
Ligation
Motivation
Neurons
Therapeutics

Keywords

  • brain reward system
  • Chronic pain
  • DREADD
  • exercise-induced hypoalgesia
  • mesolimbic dopaminergic network
  • nucleus accumbens
  • treadmill exercise
  • ventral tegmental area

ASJC Scopus subject areas

  • Molecular Medicine
  • Cellular and Molecular Neuroscience
  • Anesthesiology and Pain Medicine

Cite this

Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise : A study for specific neural control with Gi-DREADD in mice. / Wakaizumi, Kenta; Kondo, Takashige; Hamada, Yusuke; Narita, Michiko; Kawabe, Rui; Narita, Hiroki; Watanabe, Moe; Kato, Shigeki; Senba, Emiko; Kobayashi, Kazuto; Kuzumaki, Naoko; Yamanaka, Akihiro; Morisaki, Hiroshi; Narita, Minoru.

In: Molecular Pain, Vol. 12, 01.11.2016.

Research output: Contribution to journalArticle

Wakaizumi, K, Kondo, T, Hamada, Y, Narita, M, Kawabe, R, Narita, H, Watanabe, M, Kato, S, Senba, E, Kobayashi, K, Kuzumaki, N, Yamanaka, A, Morisaki, H & Narita, M 2016, 'Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise: A study for specific neural control with Gi-DREADD in mice', Molecular Pain, vol. 12. https://doi.org/10.1177/1744806916681567
Wakaizumi, Kenta ; Kondo, Takashige ; Hamada, Yusuke ; Narita, Michiko ; Kawabe, Rui ; Narita, Hiroki ; Watanabe, Moe ; Kato, Shigeki ; Senba, Emiko ; Kobayashi, Kazuto ; Kuzumaki, Naoko ; Yamanaka, Akihiro ; Morisaki, Hiroshi ; Narita, Minoru. / Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise : A study for specific neural control with Gi-DREADD in mice. In: Molecular Pain. 2016 ; Vol. 12.
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abstract = "Background: 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. Methods: 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. Results: 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. Conclusion: 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.",
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AU - Kondo, Takashige

AU - Hamada, Yusuke

AU - Narita, Michiko

AU - Kawabe, Rui

AU - Narita, Hiroki

AU - Watanabe, Moe

AU - Kato, Shigeki

AU - Senba, Emiko

AU - Kobayashi, Kazuto

AU - Kuzumaki, Naoko

AU - Yamanaka, Akihiro

AU - Morisaki, Hiroshi

AU - Narita, Minoru

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N2 - Background: 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. Methods: 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. Results: 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. Conclusion: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusion: 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.

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KW - ventral tegmental area

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