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 4

TRPV1 mediates retinoid-evoked CGRP release and paw edema.

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TRPV1 mediates retinoid-evoked CGRP release and paw edema. (A) AM580 (30...
(A) AM580 (30 μM), 9-cis-RA (300 μM), and ATRA (1000 μM) increased CGRP levels in the perfusates from rat colon segments. AMG9810 (1 μM) significantly reduced the effect of all retinoids tested (n = 6). *P < 0.05 and ***P < 0.001 versus vehicle; +P < 0.05 and +++P < 0.001 versus AMG9810. (B) Intraplantar injections of 20 μl of each AM580 (100 nmol), 9-cis-RA (100 nmol), or ATRA (600 nmol) significantly increased paw volume compared with that injected with vehicle controls. The paw edema ratio is the percentage increase of paw volume induced by retinoids. The effects of retinoids were markedly attenuated by AMG9810 (30 mg/kg, i.p. injection) or abolished in the Trpv1–/– mice. *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle; +P < 0.05, ++P < 0.01 versus AMG9810; #P < 0.05, ###P < 0.001 versus Trpv1–/–. n = 6–10 animals per condition.