Silencing of vanilloid receptor TRPV1 by RNAi reduces neuropathic and visceral pain in vivo Thomas Christoph a,1 , Arnold Gru ¨ nweller b,c,1 , Joanna Mika d,e , Martin K.-H. Scha ¨fer d , Erik J. Wade a , Eberhard Weihe d , Volker A. Erdmann b , Robert Frank a , Clemens Gillen a , Jens Kurreck b, * a Research and Development, Gru ¨ nenthal GmbH, Aachen, Germany b Institute for Chemistry and Biochemistry, Free University Berlin, Germany c Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Germany d Institute of Anatomy and Cell Biology, Philipps-University Marburg, Germany e Institute of Pharmacology, Polish Academy of Sciences, Krako ´ w, Poland Received 8 September 2006 Available online 18 September 2006 Abstract RNA interference (RNAi) has proven to be a powerful technique to study the function of genes by producing knock-down pheno- types. Here, we report that intrathecal injection of an siRNA against the transient receptor potential vanilloid receptor 1 (TRPV1) reduced cold allodynia of mononeuropathic rats by more than 50% over a time period of approximately 5 days. A second siRNA tar- geted to a different region of the TRPV1 gene was employed and confirmed the analgesic action of a TRPV1 knock-down. Furthermore, siRNA treatment diminished spontaneous visceral pain behavior induced by capsaicin application to the rectum of mice. The analgesic effect of siRNA-mediated knockdown of TRPV1 in the visceral pain model was comparable to that of the low-molecular weight receptor antagonist BCTC. Our data demonstrate that TRPV1 antagonists, including TRPV1 siRNAs, have potential in the treatment of both, neuropathic and visceral pain. Ó 2006 Elsevier Inc. All rights reserved. Keywords: BCTC; Capsaicin; Neuropathic pain; RNA interference; Small interfering RNA; Vanilloid receptor; Visceral pain Chronic pain affects more than 320 million people worldwide [1], but current pharmaceutical treatment of pain sufferers is frequently unsatisfactory, demonstrating the obvious need to develop new strategies for the treat- ment of pain with acceptable adverse side effects [2]. One of the major new targets for novel pain medication is TRPV1, which is activated by heat, protons, and capsaicin, the hot component of chili peppers [3,4]. Its sensitivity is further modulated and increased by pathophysiological states such as inflammation [5]. TRPV1 has thus been con- sidered to be a central integrator of numerous endogenous and exogenous stimuli [6,7]. As a result of the findings that demonstrated the impor- tant function of TRPV1 in pain perception, low molecular weight compounds have been developed that modulate the activity of the receptor and attenuate inflammatory pain conditions in rodents (summarized in [8]). The role of TRPV1 during neuropathic pain, however, is not fully clar- ified, although the potent TRPV1 antagonist BCTC has been shown to reduce mechanical hyperalgesia and allo- dynia in neuropathic pain models [9]. RNA interference (RNAi) has been established as a powerful technique to investigate gene functions. For this purpose, small interfering RNA (siRNA) molecules 21 nucleotides in length are usually employed to specifically 0006-291X/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2006.09.037 * Corresponding author. Fax: +49 30 83856413. E-mail address: jkurreck@chemie.fu-berlin.de (J. Kurreck). 1 These authors contributed equally to this work. www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 350 (2006) 238–243 BBRC