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The Journal of Neuroscience, May 7, 2008, 28(19):4949-4956; doi:10.1523/JNEUROSCI.0323-08.2008

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Neurobiology of Disease
P2Y₁₂ Receptors in Spinal Microglia Are Required for Neuropathic Pain after Peripheral Nerve Injury

Hidetoshi Tozaki-Saitoh,¹ Makoto Tsuda,¹ Hiroyuki Miyata,¹ Kazuaki Ueda,¹ Shinichi Kohsaka,² and Kazuhide Inoue¹

¹Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi, Fukuoka 812-8582, Japan, and ²Department of Neurochemistry, National Institute of Neuroscience, Kodaira, Tokyo 187-8502, Japan

Correspondence should be addressed to Dr. Kazuhide Inoue, Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan. Email: inoue{at}phar.kyushu-u.ac.jp

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 P2Y₁₂R 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.

Key words: P2Y₁₂ receptor; microglia; neuropathic pain; purinergic; spinal cord; analgesia

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Received Sept. 13, 2007; revised March 13, 2008; accepted March 31, 2008.

Correspondence should be addressed to Dr. Kazuhide Inoue, Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan. Email: inoue{at}phar.kyushu-u.ac.jp

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