%0 Journal Article %1 dore-savard_central_2008 %A Doré-Savard, Louis %A Roussy, Geneviève %A Dansereau, Marc-André %A Collingwood, Michael A %A Lennox, Kim A %A Rose, Scott D %A Beaudet, Nicolas %A Behlke, Mark A %A Sarret, Philippe %D 2008 %J Molecular Therapy: The Journal of the American Society of Gene Therapy %K Animals Cricetinae Cricetulus Ganglia Male Neurotensin Oligonucleotides Pain Rats Receptors Ribonuclease_{III} Small_Interfering Spinal {CHO}_Cells {RNA} {RNA}_Interference {Sprague-Dawley} %N 7 %P 1331--1339 %R 10.1038/mt.2008.98 %T Central delivery of Dicer-substrate siRNA: a direct application for pain research %U http://www.ncbi.nlm.nih.gov/pubmed/18523447 %V 16 %X RNA interference (RNAi) is gaining acceptance as a potential therapeutic strategy against peripheral disease, and several clinical trials are already underway with 21-mer small-interfering RNA (siRNA) as the active pharmaceutical agent. However, for central affliction like pain, such innovating therapies are limited but nevertheless crucial to improve pain research and management. We demonstrate here the proof-of-concept of the use of 27-mer Dicer-substrate siRNA (DsiRNA) for silencing targets related to CNS disorders such as pain states. Indeed, low dose DsiRNA (0.005 mg/kg) was highly efficient in reducing the expression of the neurotensin receptor-2 (NTS2, a G-protein-coupled receptor (GPCR) involved in ascending nociception) in rat spinal cord through intrathecal (IT) administration formulated with the cationic lipid i-Fect. Along with specific decrease in NTS2 mRNA and protein, our results show a significant alteration in the analgesic effect of a selective-NTS2 agonist, reaching 93\% inhibition up to 3-4 days after administration of DsiRNA. In order to ensure that these findings were not biased by unsuspected off-target effects (OTEs), we also demonstrated that treatment with a second NTS2-specific DsiRNA also reversed NTS2-induced antinociception, and that NTS2-specific 27-mer duplexes did not alter signaling through NTS1, a closely related receptor. Altogether, DsiRNAi represents a potent tool for dissecting nociceptive pathways and could further lead to a new class of central active drugs.

@article{dore-savard_central_2008, abstract = {{RNA} interference {(RNAi)} is gaining acceptance as a potential therapeutic strategy against peripheral disease, and several clinical trials are already underway with 21-mer small-interfering {RNA} {(siRNA)} as the active pharmaceutical agent. However, for central affliction like pain, such innovating therapies are limited but nevertheless crucial to improve pain research and management. We demonstrate here the proof-of-concept of the use of 27-mer Dicer-substrate {siRNA} {(DsiRNA)} for silencing targets related to {CNS} disorders such as pain states. Indeed, low dose {DsiRNA} (0.005 mg/kg) was highly efficient in reducing the expression of the neurotensin receptor-2 {(NTS2}, a G-protein-coupled receptor {(GPCR)} involved in ascending nociception) in rat spinal cord through intrathecal {(IT)} administration formulated with the cationic lipid {i-Fect.} Along with specific decrease in {NTS2} {mRNA} and protein, our results show a significant alteration in the analgesic effect of a {selective-NTS2} agonist, reaching 93\% inhibition up to 3-4 days after administration of {DsiRNA.} In order to ensure that these findings were not biased by unsuspected off-target effects {(OTEs)}, we also demonstrated that treatment with a second {NTS2-specific} {DsiRNA} also reversed {NTS2-induced} antinociception, and that {NTS2-specific} 27-mer duplexes did not alter signaling through {NTS1}, a closely related receptor. Altogether, {DsiRNAi} represents a potent tool for dissecting nociceptive pathways and could further lead to a new class of central active drugs.}, added-at = {2011-08-03T17:38:07.000+0200}, author = {{Doré-Savard}, Louis and Roussy, Geneviève and Dansereau, {Marc-André} and Collingwood, Michael A and Lennox, Kim A and Rose, Scott D and Beaudet, Nicolas and Behlke, Mark A and Sarret, Philippe}, biburl = {https://www.bibsonomy.org/bibtex/2c9853247963f73a7386432e25ff7e761/crc_chus}, doi = {10.1038/mt.2008.98}, interhash = {7befa81fff4258fd09e601fac407da0e}, intrahash = {c9853247963f73a7386432e25ff7e761}, issn = {1525-0024}, journal = {Molecular Therapy: The Journal of the American Society of Gene Therapy}, keywords = {Animals Cricetinae Cricetulus Ganglia Male Neurotensin Oligonucleotides Pain Rats Receptors Ribonuclease_{III} Small_Interfering Spinal {CHO}_Cells {RNA} {RNA}_Interference {Sprague-Dawley}}, month = jul, note = {{PMID:} 18523447}, number = 7, pages = {1331--1339}, shorttitle = {Central delivery of Dicer-substrate {siRNA}}, timestamp = {2011-08-03T20:52:19.000+0200}, title = {Central delivery of Dicer-substrate {siRNA:} a direct application for pain research}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18523447}, volume = 16, year = 2008 }