P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury

Hidetoshi Tozaki-Saitoh, Makoto Tsuda, Hiroyuki Miyata, Kazuaki Ueda, Shinichi Kohsaka, Kazuhide Inoue

Research output: Contribution to journalArticlepeer-review

245 Citations (Scopus)


Extracellular nucleotides have been implicated as signaling molecules used by microglia to sense adverse physiological conditions, such as neuronal damage. They act through purinoceptors, especially the G-protein-coupled P2Y receptor P2Y12R. Emerging evidence has indicated that activated spinal microglia responding to nerve injury are key cellular intermediaries in the resulting highly debilitating chronic pain state, namely neuropathic pain. However, the role of microglial P2Y12Rs in neuropathic pain remains unknown. Here, we show that the level of P2Y12R mRNA expression was markedly increased in the spinal cord ipsilateral to the nerve injury and that this expression was highly restricted to ionized binding calcium adapter molecule 1-positive microglia. An increase in the immunofluorescence of P2Y 12R protein in the ipsilateral spinal cord was also observed after nerve injury, and P2Y12R-positive cells were double labeled with the microglial marker OX-42. Blocking spinal P2Y12R by the intrathecal administration of its antagonist AR-C69931MX prevented the development of tactile allodynia (pain hypersensitivity to innocuous stimuli), a hallmark of neuropathic pain syndrome. Furthermore, mice lacking P2ry12 (P2ry12-/-) displayed impaired tactile allodynia after nerve injury without any change in basal mechanical sensitivity. Moreover, a single intrathecal administration of AR-C69931MX or oral administration of clopidogrel (a P2Y12R blocker clinically in use) to nerve-injured rats produced a striking alleviation of existing tactile allodynia. Together, our findings indicate that activation of P2Y12Rs in spinal microglia may be a critical event in the pathogenesis of neuropathic pain and suggest that blocking microglial P2Y12R might be a viable therapeutic strategy for treating neuropathic pain.

Original languageEnglish
Pages (from-to)4949-4956
Number of pages8
JournalJournal of Neuroscience
Issue number19
Publication statusPublished - May 7 2008

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)


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