Analgesic profile of intrathecal P2X3 antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats

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Abstract
Ciceptive C-fibers and its implication in pain processing is supported by an altered nociceptive phenotype in P2X3 knock-out mice. In order to further characterize the role of P2X3 receptor activation in nociception, we evaluated the effects of continuous intrathecal administration of P2X3 antisense oligonucleotides for 7 days in the rat. P2X3 receptor antisense oligonucleotide treatment significantly decreased nociceptive behaviors observed after injection of complete Freund's adjuvant (CFA), formalin or αβ-methylene ATP into the rat's hind paw. The anti-hyperalgesic effects of the antisense treatment in the CFA model of inflammatory pain were dose related. Similar effects were observed with two distinct P2X3 antisense oligonucleotides. These behavioral effects were significantly correlated with a decrease in P2X3 receptor protein expression in the dorsal root ganglia (DRG). In contrast, a decrease in P2X3 receptor protein expression in the DRG did not affect nociceptive behavior in the carrageenan model of acute thermal hyperalgesia. P2X3 receptor antisense oligonucleotide treatment also significantly reduced mechanical allodynia observed after spinal nerve ligation. Overall, the present data demonstrate that activation of P2X3 receptors contribute to the expression of chronic inflammatory and neuropathic pain states and that relief form these forms of chronic pain might be achieved by selective blockade of P2X3 receptor expression or activation....