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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.

SUBMITTER: Yin S

PROVIDER: S-EPMC3754244 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity.

Yin Shijin S Luo Jialie J Qian Aihua A Du Junhui J Yang Qing Q Zhou Shentai S Yu Weihua W Du Guangwei G Clark Richard B RB Walters Edgar T ET Carlton Susan M SM Hu Hongzhen H

The Journal of clinical investigation 20130808 9

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 ...[more]

PMID: 23925292

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Project description:Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage" compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations. Furthermore, intracerebroventricular injection of JZL184 produced TRPV1-dependent antinociception in the mouse formalin test. Our results show that intact 2-arachidonoylglycerol and 1-arachidonoylglycerol are endogenous TRPV1 activators, contributing to phospholipase C-dependent TRPV1 channel activation and TRPV1-mediated antinociceptive signaling in the brain.

Project description:BackgroundPrevious research using the Sensory Perception Quotient (SPQ) has reported greater sensory hypersensitivity in people with autism spectrum condition (ASC) compared to controls, consistent with other research. However, current scoring of the SPQ does not differentiate between hyper and hyposensitivity, making it uncertain whether individuals with ASC might also show differences in hyposensitivity. Furthermore, no research to date has focused on sensory differences in females, and whether differences in sensory sensitivity extend to the broader autism phenotype (BAP). The present study aimed to fill these gaps.MethodsThe present study developed and validated a Revised Scoring of the Sensory Perception Quotient (SPQ-RS) in order to investigate self-reported hypersensitivity and hyposensitivity in three groups of adults: a female ASC group (n = 152), mothers of children with ASC (BAP mothers group; n = 103), and a control mothers group (n = 74). All participants completed the SPQ as a self-report measure of sensory processing and the Autism-Spectrum Quotient (AQ) as a measure of the degree of autism traits.ResultsThe female ASC group reported significantly more hypersensitivity, but not more hyposensitivity, compared to the control female and BAP mothers groups. The BAP mothers group did not differ from the control mothers group in either reported hypersensitivity (p = .365) or hyposensitivity (p = .075), suggesting atypical sensory sensitivity is not a BAP trait within females. SPQ-RS hypersensitivity scores positively correlated with autistic traits in the female ASC (r = .266) and BAP mothers groups (r = .350).ConclusionsThe present findings revealed greater sensory hypersensitivity, but not hyposensitivity, in females with ASC compared to BAP and control female groups, and that a greater degree of autism traits relates to higher hypersensitivity in ASC females. The results offer support for the enhanced perceptual functioning model using large samples of females, who are an understudied population, and demonstrate the validity of the SPQ-RS as a valuable new research tool for exploring self-reported hypersensitivity and hyposensitivity.

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Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity.

Publications

Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity.

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