Surfactant cocamide monoethanolamide causes eye irritation by activating nociceptor TRPV1 channels

Abstract

Background and Purpose Cocamide monoethanolamide (CMEA) is commonly used as a surfactant‐foam booster in cosmetic formulations. Upon contact with the eye or other sensitive skin areas, CMEA elicits stinging and lasting irritation. We hypothesized a specific molecular interaction with TRPV1 channels by which CMEA caused eye irritation. Experimental Approach Eye irritancy was evaluated using eye‐wiping tests in rabbits and mice. Intracellular Ca2+ concentrations and action potentials were measured using Ca2+ imaging and current clamp respectively. Voltage clamp, site‐direct mutagenesis and molecular modelling were used to identify binding pockets for CMEA on TRPV1 channels. Key Results CMEA‐induced eye irritation is ameliorated by selective ablation of TRPV1 channels.Rodents exhibit much stronger responses to CMEA than rabbits. In trigeminal ganglion neurons, CMEA induced Ca2+ influx and neuronal excitability, effects mitigated by a TRPV1 channel inhibition and absent in TRPV1 knockout neurons. In HEK‐293 cells expressing TRPV1 channels, CMEA increased whole‐cell currents by increasing channel open probability (EC50 = 10.2 μM), without affecting TRPV2, TRPV3, TRPV4, and TRPA1 channel activities. Lauric acid monoethanolamide (LAMEA), the most abundant constituent of CMEA, was the most efficacious and potent TRPV1 channel activator, binding to the capsaicin‐binding pocket of the channel. The T550I mutants of rabbit and human TRPV1 channels exhibit much lower sensitivity to LAMEA. Conclusions and Implication CMEA directly activates TRPV1 channels to produce eye irritation. Rabbits, the standard animal used for eye irritancy tests are poor models for evaluating human eye irritants structurally related to CMEA. Our study identifies potential alternatives to CMEA as non‐irritating surfactants.

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“…HaCaT cells (RRID:CVCL_0038) were maintained in DMEM supplemented with 10% fetal bovine serum (FBS) and 1% penicillin–streptomycin (P/S). HEK‐293 cells stably expressing human (h)TRPV1, mouse (m)TRPV2, mTRPV3, hTRPV4, hTRPM8, or hTRPA1 were generated in our lab as previously described (Zhao et al, 2021). HEK‐293 cells expressing hTRPV1, mTRPV2, mTRPV3, or hTRPV4 were maintained in DMEM supplemented with 10% FBS, 1% P/S and 500 μg·ml −1 G418 whereas HEK‐293 cells expressing hTRPA1 or hTRPM8 were maintained in DMEM supplemented with 10% FBS, 1% P/S, 5 μg·ml −1 blasticidin and 50 μg·ml −1 hygromycin B.…”

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“…Y axis is labelling in figures using ‘fold matched control values’. Based on the variance of our previously published studies with similar protocols, the present studies are adequately powered with 6 or 10 animals per group (Zhao & Wang, 2021). Statistical significance was determined using t ‐test, ordinary or repeated one‐way ANOVA, and only if F in ANOVA achieved P value < 0.05, a post hoc Bonferroni comparison was conducted.…”

“…Action potentials in adult rat small-and medium-sized (<35 μm in diameter) L 4-6 DRG neurons were recorded by current clamp experiments using an EPC-10 amplifier (HEKA Electronics, Germany, RRID: SCR_014270) as described previously (F. Zhao et al, 2019;F. Zhao & Wang, 2021).…”

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