Neuropathic pain, a highly debilitating pain condition that commonly occurs after nerve damage, is a reflection of the aberrant excitability of dorsal horn neurons. This pathologically altered neurotransmission requires a communication with spinal microglia activated by nerve injury. However, how normal resting microglia become activated remains unknown. Here we show that in naive animals spinal microglia express a receptor for the cytokine IFN-␥ (IFN-␥R) in a cell-type-specific manner and that stimulating this receptor converts microglia into activated cells and produces a long-lasting pain hypersensitivity evoked by innocuous stimuli (tactile allodynia, a hallmark symptom of neuropathic pain). Conversely, ablating IFN-␥R severely impairs nerve injury-evoked microglia activation and tactile allodynia without affecting microglia in the contralateral dorsal horn or basal pain sensitivity. We also find that IFN-␥-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X 4 receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-␥R-dependent microglial and behavioral alterations. These results suggest that IFN-␥R is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.allodynia ͉ cytokine ͉ glia ͉ Lyn tyrosine kinase ͉ purinergic receptor

Neuropathic pain, a highly debilitating condition that commonly occurs after damage to the nervous system, is often resistant to commonly used analgesic agents such as non-steroidal anti-inflammatory drugs and even opioids. Several studies using rodent models reported that cannabinoid CB 2 receptor (CB 2 R) agonists are effective for treating chronic pain. However, the analgesic mechanism of CB 2 R agonists in neuropathic pain states is not fully understood. In this study, we investigated the role of CB 2 Rs in the development and maintenance phases of neuropathic pain, and the mechanism of the CB 2 R-mediated analgesic effect on neuropathic pain. In a rat model of neuropathic pain, systemic administration of JWH133, a CB 2 R agonist, markedly improved tactile allodynia, and this effect was prevented by intrathecal pretreatment with AM630, a CB 2 R antagonist. The antiallodynic effect of intrathecally administered JWH133 was inhibited by intrathecal pretreatment with pertussis toxin or forskolin. In the spinal cord, CB 2 R expression was significantly increased on post-operative day 3, and persisted for 2 weeks. Furthermore, repeated intrathecal administration of JWH133 notably attenuated the development of tactile allodynia after peripheral nerve injury. In a culture of microglia activated by overexpressing interferon regulatory factor 8, a transcription factor crucial for neuropathic pain, JWH133 treatment suppressed the increased expression of interleukin-1 . Our findings suggest that activation of CB 2 Rs upregulated in the spinal cord after nerve injury alleviates existing tactile allodynia through the G i/oadenylate cyclase signaling pathway and suppresses the development of allodynia. This process may reduce the inflammatory response of microglia. Therefore, spinal CB 2 Rs may be a therapeutic target for the treatment of neuropathic pain.

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