Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer

Moe Watanabe, Michiko Narita, Yusuke Hamada, Akira Yamashita, Hideki Tamura, Daigo Ikegami, Takashige Kondo, Tatsuto Shinzato, Takatsune Shimizu, Yumi Fukuchi, Akihiro Muto, Hideyuki Okano, Akihiro Yamanaka, Vivianne L. Tawfik, Naoko Kuzumaki, Edita Navratilova, Frank Porreca, Minoru Narita

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15 Citations (Scopus)

Abstract

Chronic pain induced by nerve damage due to trauma or invasion of cancer to the bone elicits severe ongoing pain as well as hyperalgesia and allodynia likely reflecting adaptive changes within central circuits that amplify nociceptive signals. The present study explored the possible contribution of the mesolimbic dopaminergic circuit in promoting allodynia related to neuropathic and cancer pain. Mice with ligation of the sciatic nerve or treated with intrafemoral osteosarcoma cells showed allodynia to a thermal stimulus applied to the paw on the injured side. Patch clamp electrophysiology revealed that the intrinsic neuronal excitability of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (N.Acc.) was significantly reduced in those mice. We used tyrosine hydroxylase (TH)-cre mice that were microinjected with adeno-associated virus (AAV) to express channelrhodopsin-2 (ChR2) to allow optogenetic stimulation of VTA dopaminergic neurons in the VTA or in their N.Acc. terminals. Optogenetic activation of these cells produced a significant but transient anti-allodynic effect in nerve injured or tumor-bearing mice without increasing response thresholds to thermal stimulation in sham-operated animals. Suppressed activity of mesolimbic dopaminergic neurons is likely to contribute to decreased inhibition of N.Acc. output neurons and to neuropathic or cancer pain-induced allodynia suggesting strategies for modulation of pathological pain states.

Original languageEnglish
JournalMolecular Pain
Volume14
DOIs
Publication statusPublished - 2018 Jan 1

Keywords

  • Neuropathic pain
  • cancer pain
  • dopamine
  • mesolimbic dopaminergic neurons
  • optogenetics

ASJC Scopus subject areas

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

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    Watanabe, M., Narita, M., Hamada, Y., Yamashita, A., Tamura, H., Ikegami, D., Kondo, T., Shinzato, T., Shimizu, T., Fukuchi, Y., Muto, A., Okano, H., Yamanaka, A., Tawfik, V. L., Kuzumaki, N., Navratilova, E., Porreca, F., & Narita, M. (2018). Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer. Molecular Pain, 14. https://doi.org/10.1177/1744806918756406