siRNA relieves chronic neuropathic pain

G Dorn, S Patel, G Wotherspoon… - Nucleic acids …, 2004 - academic.oup.com
G Dorn, S Patel, G Wotherspoon, M Hemmings‐Mieszczak, J Barclay, FJC Natt, P Martin…
Nucleic acids research, 2004academic.oup.com
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 P2X 3, showed diminished pain …
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 P2X 3 , 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 P2X 3 siRNA, MS siRNA or vehicle. Molecular analysis of tissues revealed that P2X 3 mRNA expressed in dorsal root ganglia, and P2X 3 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.
Oxford University Press