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The Journal of Neuroscience, January 16, 2008, 28(3):576-586; doi:10.1523/JNEUROSCI.4772-07.2008

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Cellular/Molecular
Transient Receptor Potential Channels in Sensory Neurons Are Targets of the Antimycotic Agent Clotrimazole

Victor Meseguer,^1,2 Yuji Karashima,¹ Karel Talavera,¹ Dieter D'Hoedt,¹ Tansy Donovan-Rodríguez,² Felix Viana,² Bernd Nilius,¹ and Thomas Voets¹

¹Laboratory of Ion Channel Research, Division of Physiology, Department of Molecular Cell Biology, Campus Gasthuisberg O&N1, KU Leuven, B-3000 Leuven, Belgium, and ²Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain

Correspondence should be addressed to Thomas Voets at the above address. Email: thomas.voets{at}med.kuleuven.be

Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [(N-(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin- and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC₅₀) of inward TRPM8 current was 200 nM, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.

Key words: TRP channels; sensory neurons; clotrimazole; temperature sensing; pain; chemoreceptor

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Received March 20, 2007; revised Nov. 23, 2007; accepted Nov. 26, 2007.

Correspondence should be addressed to Thomas Voets at the above address. Email: thomas.voets{at}med.kuleuven.be

This article has been cited by other articles:

				G. Bartolommei, N. Devaux, F. Tadini-Buoninsegni, M. Moncelli, and H.-J. Apell Effect of Clotrimazole on the Pump Cycle of the Na,K-ATPase Biophys. J., August 15, 2008; 95(4): 1813 - 1825. [Abstract] [Full Text] [PDF]

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