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

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 patholo...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-08, Vol.114 (31), p.E6297-E6305
Main Authors: Kato, Yuri, Hiasa, Miki, Ichikawa, Reiko, Hasuzawa, Nao, Kadowaki, Atsushi, Iwatsuki, Ken, Shima, Kazuhiro, Endo, Yasuo, Kitahara, Yoshiro, Inoue, Tsuyoshi, Nomura, Masatoshi, Omote, Hiroshi, Moriyama, Yoshinori, Miyaji, Takaaki
Format: Article
Language:English
Subjects:
Abnormalities
Adenosine triphosphatase
Adenosine triphosphate
Allosteric properties
Analgesics
Biological Sciences
Bisphosphonates
Chemical compounds
Chlorides
Chronic pain
Clodronic acid
Immune system
Immunosuppressive agents
Inflammation
Medical treatment
Microglia
Neuralgia
Pain
Pain perception
Pharmacology
PNAS Plus
Side effects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1704847114