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Published online 16 March 2004

Nucleic Acids Research, 2004, Vol. 32, No. 5 e49
© 2004 Oxford University Press

siRNA relieves chronic neuropathic pain

Gabriele Dorn, Sadhana Patel1, Glen Wotherspoon1, Maja Hemmings-Mieszczak, Jane Barclay1, Francois J. C. Natt, Pierre Martin, Stuart Bevan1, Alyson Fox1, Pam Ganju1, William Wishart* and Jonathan Hall

Functional Genomics, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland and 1 Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BS, UK

*To whom correspondence should be addressed. Tel: +41 61 324 7886; Fax: +41 61 324 5474; Email: william.wishart{at}pharma.novartis.com
Present address:
Pierre Martin, Solvias AG, Klybeckstr. 191, CH-4002 Basel, Switzerland

Double stranded, short interfering RNAs (siRNA) of 21–22 nt length initiate a sequence-specific, post-trancriptional gene silencing in animals and plants known as RNA interference (RNAi). Here we show that RNAi can block a pathophysiological pain response and provide relief from neuropathic pain in a rat disease model by down regulating an endogenous, neuronally expressed gene. Rats, intrathecally infused with a 21 nt siRNA perfectly complementary to the pain-related cation-channel P2X3, showed diminished pain responses compared to missense (MS) siRNA-treated and untreated controls in models of both agonist-evoked pain and chronic neuropathic pain. This form of delivery caused no adverse effects in any of the animals receiving P2X3 siRNA, MS siRNA or vehicle. Molecular analysis of tissues revealed that P2X3 mRNA expressed in dorsal root ganglia, and P2X3 protein translocated into the dorsal horn of the spinal cord, were significantly diminished. These observations open a path toward use of siRNA as a genetic tool for drug target validation in the mammalian central nervous system, as well as for proof of concept studies and as therapeutic agents in man.


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