RESEARCHOpen Access Modulation of TRP channels by resveratrol and other stilbenoids Lina Yu1,2, Shenglan Wang1,2,3, Yoko Kogure1,2, Satoshi Yamamoto1, Koichi Noguchi2and Yi Dai1,2,3* Abstract Background: Resveratrol (3,5,4 - trihydroxy-trans-stilbene), a widely distributed natural stilbenoid, was proposed to account for the unique effects of red wine on life span and health. It has been reported to possess various biological and pharmacological activities, such as anti-oxidant, anti-inflammatory, and anti-carcinogenic effects. Here, using whole-cell patch-clamp techniques and behavioral analyses, we investigated whether resveratrol and other stilbenoids can modulate TRP channels in sensory neurons in vitro, and have analgesic effects in vivo. Results: We found that resveratrol dose-dependently suppressed the allyl isothiocyanate (AITC)-induced currents (IAITC) in HEK293 cells that express TRPA1, as well as in rat dorsal root ganglion (DRG) neurons. Instead, pinosylvin methyl ether (PME), another derivate of stilbene which has a similar structure to resveratrol, dose-dependently blocked the capsaicin-induced currents (ICAP) in HEK293 cells that express TRPV1 as well as in DRG neurons. Interestingly, resveratrol had no inhibitory effect on the ICAP, and PME had no effect on the IAITC. Otherwise, trans- stilbene showed no any effect on IAITCor ICAP. The concentration response curve of AITC showed that resveratrol inhibited the action of TRPA1 not by changing the EC50, but by suppressing the AITC-induced maximum response. By contrast, the inhibition of TRPV1 by PME did not change the capsaicin-induced maximum response but did cause a right shift of the EC50. Moreover, pre-administration of resveratrol suppressed intraplantar injections of AITC- evoked nocifensive behaviors, as well as that PME suppressed capsaicin-evoked one. Conclusions: These data suggest that resveratrol and other stilbenoids may have an inhibitory effect on TRP channels. In addition, these stilbenoids modulate TRP channel activity in different ways. Background Stilbenoids are bioactive compounds that show beneficial effects on human health, such as anti-tumor activity and increased rate of survival. Resveratrol (3,5,4 - trihydroxy- trans-stilbene) is a representative stilbenoid which consists of two aromatic rings that are attached by a methylene bridge (Figure 1). It is a natural phenol and phytoalexin, produced biologically by 72 different plant species, espe- cially grapevines, pine trees, and legumes 1. Resveratrol was first isolated from the roots of white hellebore (Veratrum grandiflorum O. Loes), and from the roots of Polygonum cuspidatum, a plant used in traditional Chinese and Japanese medicine 2,3. The concentration of resveratrol in grapes skin is about 0.1 mg/100 g of fresh weight 4. Resveratrol has been reported to have potent anti-aging, anti-inflammatory, anti-cancer anti-oxidative, and chemo-protective characteristics 5-11. Recently, some studies have indicated that resveratrol has analgesic proper- ties against both acute and chronic pain that is triggered by nocifensive stimuli, inflammation, or nerve-injury 9-14. Mechanisms of this analgesic action have been suggested to be alterations of the expression of serum tumor necrosis factor-alpha, whole brain nitric oxide in the diabetic rat model 14, reduction of expression of cyclooxygenase-2 in the inflammatory pain model 10, or inhibition of cyclin- dependent kinase 5 activity in primary afferent neurons 15. However, the direct molecular target of resveratrol has been elusive. Since the discovery of the Drosophila melanogaster transient receptor potential (trp) gene, it has become known that mammalian genomes contain 28 homolo- gous genesencoding proteins thatarecapableof forming a large variety of cationic channels, usually with * Correspondence: ydaihuhs.ac.jp 1Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530, Japan 2Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan Full list of author information is available at the end of the article MOLECULAR PAIN 2013 Yu et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http:/creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Yu et al. Molecular Pain 2013, 9:3 http:/www.molecularpain.com/content/9/1/3 permeability to sodium and calcium 16. TRPV1 and TRPA1 are members of branch V and A of the TRP fam- ily of cation channels respectively, and are expressed by a subset of small-sized DRG or trigeminal ganglia neurons in neonatal rats, adult rats and mice 17,18. It is well known that TRPV1 is activated by capsaicin, protons, or heat (with a thermal threshold 43?C), which cause pain in