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The Journal of Neuroscience, September 15, 2002, 22(18):8139-8147
Functional Downregulation of P2X3 Receptor Subunit in
Rat Sensory Neurons Reveals a Significant Role in Chronic Neuropathic
and Inflammatory Pain
Jane
Barclay1,
Sadhana
Patel1,
Gabriele
Dorn2,
Glen
Wotherspoon1,
Sarah
Moffatt1,
Louise
Eunson1,
Samir
Abdel'al2,
Francois
Natt2,
Jonathan
Hall2,
Janet
Winter1,
Stuart
Bevan1,
William
Wishart2,
Alyson
Fox1, and
Pam
Ganju1
1 Novartis Institute for Medical Sciences, London WC1E
6BS, United Kingdom, and 2 Functional Genomics, Novartis
Pharma AG, CH-4002 Basel, Switzerland
The excitation of nociceptive sensory neurons by ATP released in
injured tissue is believed to be mediated partly by P2X3 receptors. Although an analysis of P2X3 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 P2X3 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   -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, P2X3 protein levels were
significantly downregulated in lumbar L4 and L5 dorsal root ganglia.
After 7 d of ASO treatment, P2X3 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 Freund's 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 P2X3 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 P2X3 receptors in the
pathophysiology of chronic pain.
Key words:
dorsal root ganglia; P2X3; P2X2/3; neuropathic pain; inflammatory pain; antisense oligonucleotide; ,-methylene ATP
Copyright © 2002 Society for Neuroscience 0270-6474/02/22188139-09$05.00/0
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