Investigation of TRPV1 loss-of-function phenotypes in transgenic shRNA expressing and knockout mice

The function of the transient receptor potential vanilloid 1 (TRPV1) cation channel was analyzed with RNA interference technologies and compared to TRPV1 knockout mice. Expression of shRNAs targeting TRPV1 in transgenic (tg) mice was proven by RNase protection assays, and TRPV1 downregulation was co...

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Published in:Molecular and cellular neuroscience 2008-03, Vol.37 (3), p.579-589
Main Authors: Christoph, Thomas, Bahrenberg, Gregor, De Vry, Jean, Englberger, Werner, Erdmann, Volker A., Frech, Moritz, Kögel, Babette, Röhl, Thomas, Schiene, Klaus, Schröder, Wolfgang, Seibler, Jost, Kurreck, Jens
Format: Article
Language:English
Subjects:
Animals
Animals, Genetically Modified
Calcium - metabolism
Capsaicin - pharmacology
Diterpenes - pharmacokinetics
Ganglia, Spinal - cytology
Gene Expression - drug effects
Green Fluorescent Proteins - metabolism
Male
Mice
Neurons - drug effects
Pain Measurement - methods
Phenotype
Protein Binding - drug effects
Reaction Time - drug effects
Reaction Time - genetics
RNA Interference - physiology
RNA, Small Interfering - pharmacology
Spinal Cord - drug effects
Spinal Cord Injuries - metabolism
TRPV Cation Channels - deficiency
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Summary:The function of the transient receptor potential vanilloid 1 (TRPV1) cation channel was analyzed with RNA interference technologies and compared to TRPV1 knockout mice. Expression of shRNAs targeting TRPV1 in transgenic (tg) mice was proven by RNase protection assays, and TRPV1 downregulation was confirmed by reduced expression of TRPV1 mRNA and lack of receptor agonist binding in spinal cord membranes. Unexpectedly, TRPV3 mRNA expression was upregulated in shRNAtg but downregulated in knockout mice. Capsaicin-induced [Ca 2+] i changes in small diameter DRG neurons were significantly diminished in TRPV1 shRNAtg mice, and administration of capsaicin hardly induced hypothermia or nocifensive behaviour in vivo. Likewise, sensitivity towards noxious heat was reduced. Interestingly, spinal nerve injured TRPV1 knockout but not shRNAtg animals developed mechanical allodynia and hypersensitivity. The present study provides further evidence for the relevance of TRPV1 in neuropathic pain and characterizes RNA interference as valuable technique for drug target validation in pain research.
ISSN:1044-7431
1095-9327
DOI:10.1016/j.mcn.2007.12.006