Editors' ChoiceNeuroscience

New Targets for Pain Relief

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Science's STKE  19 Aug 2003:
Vol. 2003, Issue 196, pp. tw323-TW323
DOI: 10.1126/stke.2003.196.tw323

Persistent pain that occurs after nerve damage can be debilitating, and its management is hindered by a lack of understanding of the underlying signaling mechanisms. Tsuda et al. now provide relief, at least from some of the ignorance of mechanism, by identifying an unsuspected receptor in an unexpected cell type where it appears to have a key regulatory role. The authors used a rat model of neuropathic pain that occurs after injury of a spinal nerve in which they measured hypersensitivity to a normally innocuous touch sensation (such hypersensitivity is called allodynia). They found that sensitivity of allodynia to pharmacological inhibition had a pattern that suggested a role for the purinergic receptors known as P2X4R, membrane ion channels that are opened in response to binding of ATP. The effect of the inhibitors was specific to allodynia, and sensitivity of the animals to normal acute-pain responses was not affected. The amount of P2X4 receptor protein was increased in response to nerve injury, and immunofluorescence labeling showed that the newly synthesized receptors were expressed not on neurons, but rather in microglial cells. Reducing the increased expression of P2X4Rs by perfusion with antisense oligodeoxynucleotides to the receptor reduced allodynia in the animals. Furthermore, pain sensitivity of the animals was enhanced when rats were injected with cultured microglial cells that had been activated through their P2X4Rs. The studies offer promise for the development of therapies specific to allodynia that either prevent expression of P2X4Rs or inhibit signaling by those receptors in microglia.

M. Tsuda, Y. Shigemoto-Mogami, S. Koizumi, A. Mizokoshi, S. Kohsaka, M. W. Salter, K. Inoue, P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778-783 (2003). [Online Journal]

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