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

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 halfmaximal 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. vesicular nucleotide transporter | purinergic chemical transmission | analgesic effect | antiinflammatory effect | clodronate

Vesicular nucleotide transporter mediates ATP release and migration in neutrophils

“…A previous study indicated that clodronate inhibits vesicular ATP release, and decreases the release of inflammatory mediators, thereby attenuating chronic inflammation (24). In the present study, we found that clodronate also inhibits vesicular ATP release from neutrophils, and reduces neutrophil migration, indicating a novel mechanism through which VNUT mediates its anti-inflammatory effects (Fig.…”

“…3A). This suggests that Recently, we identified a potent allosteric inhibitor of VNUT, clodronate (24).…”

“…Neutrophils migrate to the sites of Clodronate is a specific inhibitor of VNUT, and is currently used as an anti-osteoporotic drug (24,35 …”

Purinergic drug targets for gastrointestinal disorders

“…The former possibility is supported by accumulating evidence for a role of P2X7R in nociception [Jorge et al, 2012; Ochoa-Cortes-et al, 2014]. Furthermore, a vesicular ATP release inhibitor is an effective treatment of neuropathic and inflammatory pain in mice (Kato et al, 2017), presumably by acting at P2X7R or other P2XR.…”

Microglia-Mediated Regulation of Neuropathic Pain: Molecular and Cellular Mechanisms

“…111) In addition, a chemical screening of a library identified the antidepressant duloxetine as a clinically approved drug that has an inhibitory effect on rodent and human P2X4R and a reversal effect on the PNI-induced mechanical allodynia. 112) For drugs controlling ATP release, the first-generation bisphosphonate clodronate was identified as a potent and selective allosteric inhibitor for VNUT. Clodronate impaired vesicular ATP release from neurons and attenuated neuropathic pain.…”