Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain

Yuri Kato, Miki Hiasa, Reiko Ichikawa, Nao Hasuzawa, Atsushi Kadowaki, Ken Iwatsuki, Kazuhiro Shima, Yasuo Endo, Yoshiro Kitahara, Tsuyoshi Inoue, Masatoshi Nomura, Hiroshi Omote, Yoshinori Moriyama, Takaaki Miyaji

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Abstract

Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a half-maximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl. A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT/ mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release.

Original languageEnglish
Pages (from-to)E6297-E6305
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number31
DOIs
Publication statusPublished - Aug 1 2017

All Science Journal Classification (ASJC) codes

  • General

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    Kato, Y., Hiasa, M., Ichikawa, R., Hasuzawa, N., Kadowaki, A., Iwatsuki, K., Shima, K., Endo, Y., Kitahara, Y., Inoue, T., Nomura, M., Omote, H., Moriyama, Y., & Miyaji, T. (2017). Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain. Proceedings of the National Academy of Sciences of the United States of America, 114(31), E6297-E6305. https://doi.org/10.1073/pnas.1704847114