Dorn, Gabriele, Patel, Sadhana, Wotherspoon, Glen, Hemmings-Mieszczak, Maja, Barclay, Jane, Natt, Francois, Martin, Pierre, Bevan, Stuart, Fox, Alyson, Ganju, Pam, Wishart, William L. and Hall, Jonathan (2004) siRNA relieves chronic neuropathic pain. Nucleic Acids Research, 32 (5). e49. ISSN 1362-4962

Abstract

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.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... http://www.pubmedcentral.nih.gov/article...
Additional Information:	author can archive post-print (ie final draft post-refereeing); Publisher version cannot be used except for Nucleic Acids Research articles
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... http://www.pubmedcentral.nih.gov/article...
Date Deposited:	14 Dec 2009 13:54
Last Modified:	14 Dec 2009 13:54
URI:	https://oak.novartis.com/id/eprint/770