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Functional Downregulation of P2X 3 Receptor Subunit in Rat Sensory Neurons Reveals a Significant Role in Chronic Neuropathic and Inflammatory Pain

2002; Society for Neuroscience; Volume: 22; Issue: 18 Linguagem: Inglês

10.1523/jneurosci.22-18-08139.2002

1529-2401

J. Elaine Barclay, Sadhana Patel, Gabriele Dorn, Glen Wotherspoon, Sarah Moffatt, L. H. Eunson, Samir Abdel'Al, François Natt, Jonathan Hall, Janet Winter, Stuart Bevan, William Wishart, Alyson Fox, Pam Ganju,

Pain Mechanisms and Treatments

The excitation of nociceptive sensory neurons by ATP released in injured tissue is believed to be mediated partly by P2X 3 receptors. Although an analysis of P2X 3 knock-out mice has revealed some deficits in nociceptive signaling, detailed analysis of the role of these receptors is hampered by the lack of potent specific pharmacological tools. Here we have used antisense oligonucleotides (ASOs) to downregulate P2X 3 receptors to examine their role in models of chronic pain in the rat. ASOs and control missense oligonucleotides (180 μg/d) were administered intrathecally to naive rats for up to 7 d via a lumbar indwelling cannula attached to an osmotic minipump. Functional downregulation of the receptors was confirmed by αβ-methylene ATP injection into the hindpaw, which evoked significantly less mechanical hyperalgesia as early as 2 d after treatment with ASOs relative to controls. At this time point, P2X 3 protein levels were significantly downregulated in lumbar L4 and L5 dorsal root ganglia. After 7 d of ASO treatment, P2X 3 protein levels were reduced in the primary afferent terminals in the lumbar dorsal horn of the spinal cord. In models of neuropathic (partial sciatic ligation) and inflammatory (complete Freund9s adjuvant) pain, inhibition of the development of mechanical hyperalgesia as well as significant reversal of established hyperalgesia were observed within 2 d of ASO treatment. The time course of the reversal of hyperalgesia is consistent with downregulation of P2X 3 receptor protein and function. This study demonstrates the utility of ASO approaches for validating gene targets in in vivo pain models and provides evidence for a role of P2X 3 receptors in the pathophysiology of chronic pain.