Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity
Shijin Yin, … , Susan M. Carlton, Hongzhen Hu
Shijin Yin, … , Susan M. Carlton, Hongzhen Hu
Published August 8, 2013
Citation Information: J Clin Invest. 2013;123(9):3941-3951. https://doi.org/10.1172/JCI66413.
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Research Article Dermatology

Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity

Abstract

Retinoids are structurally related derivatives of vitamin A and are required for normal vision as well as cell proliferation and differentiation. Clinically, retinoids are effective in treating many skin disorders and cancers. Application of retinoids evokes substantial irritating side effects, including pain and inflammation; however, the precise mechanisms accounting for the sensory hypersensitivity are not understood. Here we show that both naturally occurring and synthetic retinoids activate recombinant or native transient receptor potential channel vanilloid subtype 1 (TRPV1), an irritant receptor for capsaicin, the pungent ingredient of chili peppers. In vivo, retinoids produced pain-related behaviors that were either eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1 function. These findings identify TRPV1 as an ionotropic receptor for retinoids and provide cellular and molecular insights into retinoid-evoked hypersensitivity. These findings also suggest that selective TRPV1 antagonists are potential therapeutic drugs for treating retinoid-induced sensory hypersensitivity.

Authors

Shijin Yin, Jialie Luo, Aihua Qian, Junhui Du, Qing Yang, Shentai Zhou, Weihua Yu, Guangwei Du, Richard B. Clark, Edgar T. Walters, Susan M. Carlton, Hongzhen Hu

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Figure 3

TRPV1 is the sole target of retinoids in sensory nociceptors.

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TRPV1 is the sole target of retinoids in sensory nociceptors. AM580 (A–C...
AM580 (A–C), 9-cis-RA (D–F), ATRA (G–I), and capsaicin evoked [Ca2+]i responses in a subset of DRG neurons from Trpv1+/+ but not Trpv1–/–mice. (A, D, and G) Representative Fura-2 ratiometric images of cultured DRG neurons show that AM580 (A), 9-cis-RA (D), and ATRA (G) evoked [Ca2+]i responses in a subset of DRG neurons from Trpv1+/+ but not Trpv1–/– mice. The color of the neurons switching from blue to green or red indicates the increase of [Ca2+]i. (B, E, and H) Representative traces illustrate that AM580 (B), 9-cis-RA (E), ATRA (H), or capsaicin elicited [Ca2+]i responses in Trpv1+/+ but not Trpv1–/– DRG neurons. AITC evoked similar [Ca2+]i responses in both Trpv1+/+ and Trpv1–/– DRG neurons. Each trace corresponds to the change of fluorescence ratio in a single neuron. Neurons were exposed to each retinoid (5 μM AM580, 30 μM 9-cis-RA, or 300 μM ATRA), 0.3 μM capsaicin, 100 μM AITC, and 100 mM KCl for the indicated times. (C, F, and I) Percentage of DRG neurons responding to AM580 (C), 9-cis-RA (F), ATRA (I), capsaicin, AITC, and KCl in neurons isolated from Trpv1+/+ or Trpv1–/– mice (n ≥ 330 per genotype for AM580; n 350 per genotype for 9-cis-RA and ATRA).