Etidronate attenuates tactile allodynia by spinal ATP release inhibition in mice with partial sciatic nerve ligation
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Etidronate is widely used as a therapeutic agent for osteoporosis. We have recently shown that intrathecal administration of etidronate into mice produces an analgesic effect against the capsaicin-induced nociceptive behavior. However, the effect of etidronate on neuropathic pain at the spinal level remains unknown. Therefore, we examined whether etidronate attenuates pain after partial sciatic nerve ligation (PSNL). We evaluated tactile allodynia 7 days after PSNL by measuring paw withdrawal with the von Frey filament test. The mRNA and protein levels of SLC17A9 in the ipsilateral lumbar dorsal spinal cord of PSNL-operated mice were determined using real-time PCR and western blotting, respectively. PSNL-induced tactile allodynia was attenuated by oral and intrathecal administration of etidronate, with maximum efficiency at 90 and 60 min after injection, respectively. The anti-allodynic effect of intrathecally administered etidronate was completely inhibited by an intrathecal administration of adenosine triphosphate (ATP). The solute carrier family, SLC17, mediates the transport of pain transmitters, like ATP and glutamate. Indeed, we detected several members of the SLC17 family in the mouse dorsal lumbar spinal cord. Among the detected mRNAs, only Slc17a9, encoding for neuronal vesicular ATP transporter, was significantly increased upon PSNL. SLC17A9 protein levels were also significantly increased. In mice subjected to PSNL, SLC17A9 was present in neurons and microglia, but not in astrocytes of the lumbar superficial dorsal horn. Collectively, our results suggest that etidronate produces its anti-allodynic effects by inhibiting SLC17A9-dependent exocytotic ATP release from the dorsal horn in mice subjected to PSNL.
KeywordsEtidronate Solute carrier 17A9 Intrathecal administration Partial sciatic nerve ligation Neuropathic pain Mice Adenosine triphosphate Tactile allodynia Spinal cord
We thank Mr. Kazuhiro Ota, Ms. Anri Onuma, and Mr. Yosuke Satoh at the Tohoku Medical and Pharmaceutical University for their technical assistance, and Dainippon Sumitomo Pharma for providing etidronate.
RY, WN, YE, and KT designed the experiments. RY, WN, and ON performed the experiments. RY, WN, ON, and KS analyzed the data. RY, WN, KT, and YE wrote the manuscript.
This study was supported in part by JSPS KAKENHI grants [grant numbers 17K08313, 16K21311], and the Matching Fund Subsidy for Private University from the Ministry of Education, Culture, Sports, Science and Technology of Japan [grant number S1511001L].
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Conflict of interest
The authors declare that they have no conflict of interest.
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