2. Academic Validation
  3. Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain

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

  • Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6297-E6305. doi: 10.1073/pnas.1704847114.
Yuri Kato 1 2,  Miki Hiasa 2,  Reiko Ichikawa 3,  Nao Hasuzawa 4,  Atsushi Kadowaki 5,  Ken Iwatsuki 3 6,  Kazuhiro Shima 7,  Yasuo Endo 7,  Yoshiro Kitahara 3,  Tsuyoshi Inoue 5,  Masatoshi Nomura 4,  Hiroshi Omote 2,  Yoshinori Moriyama 8 2 9,  Takaaki Miyaji 8
Affiliations

Affiliations

  • 1 Advanced Science Research Center, Okayama University, Okayama 700-8530, Japan.
  • 2 Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
  • 3 Institute for Innovation, Ajinomoto Co., Inc., Kawasaki 210-5893, Japan.
  • 4 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • 5 Department of Biophysical Chemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
  • 6 Department of Nutritional Science and Food Safety, Tokyo University of Agriculture, Tokyo 156-8502, Japan.
  • 7 Division of Oral Molecular Regulation, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan.
  • 8 Advanced Science Research Center, Okayama University, Okayama 700-8530, Japan; pineal13@yahoo.co.jp miyaji-t@okayama-u.ac.jp.
  • 9 Department of Biochemistry, Matsumoto Dental University, Siojiri 399-0781, Japan.
PMID: 28720702 DOI: 10.1073/pnas.1704847114
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.

Keywords

analgesic effect; antiinflammatory effect; clodronate; purinergic chemical transmission; vesicular nucleotide transporter.

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