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 6

Pharmacological or genetic ablation of TRPV1 function abolishes retinoid-induced sensory hypersensitivity.

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Pharmacological or genetic ablation of TRPV1 function abolishes retinoid...
(A–C) Time course of thermal hypersensitivity in animals treated with AM580 (A), 9-cis-RA (B). or ATRA (C). Intraplantar injection of 10 μl of each retinoid (AM580, 2 nmol; 9-cis-RA, 3 nmol; and ATRA, 30 nmol; red traces) induced thermal hyperalgesia in Trpv1+/+ mice. AMG9810 (10 mg/kg; i.p. injection;green traces) abolished the effect of selected retinoids. Retinoid-elicited thermal hypersensitivity was also abolished in Trpv1–/– mice (blue traces). *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle; ++P < 0.01, +++P < 0.001 versus AMG9810; ##P < 0.01, ###P < 0.001 versus Trpv1–/–. (D–F) Time course of mechanical allodynia in animals treated with AM580 (D), 9-cis-RA (E), and ATRA (F). Intraplantar injection of 10 μl of each retinoid (AM580, 2 nmol; 9-cis-RA, 3 nmol; and ATRA, 30 nmol; red traces) produced mechanical hypersensitivity in Trpv1+/+ mice, which was abolished by i.p. injection of AMG9810 (10 mg/kg; green traces). Retinoid-elicited mechanical hypersensitivity was also abolished in the Trpv1–/– mice (blue traces). *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle; +P < 0.05, ++P < 0.01, +++P < 0.001 versus AMG9810; and #P < 0.05, #P < 0.01 versus Trpv1–/–. Please note that no effect was observed upon injection of 10 μl vehicle alone (0.9% saline; black traces). n = 5–10 animals per condition. Baseline values for mechanical and thermal testing are listed in Supplemental Table 2.