Combining topical agonists with the recording of event-related brain potentials to probe the functional involvement of TRPM8, TRPA1 and TRPV1 in heat and cold transduction in the human skin

Courtin, Arthur;Mouraux, André
(2021) IASP 2021 Virtual World Congress on Pain (16.June.2021)

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Background and Aims: TRP channels play a central role in the transduction of thermal and nociceptive stimuli by free nerve endings. Most of the research on these channels has been conducted in vitro or in vivo in non-human animals and translation of these results to humans must account for potential experimental biases and interspecific differences. This study aimed at evaluating the involvement of TRPM8, TRPA1 and TRPV1 channels in the transduction of innocuous cold and noxious heat stimuli by the human thermonociceptive system. To do so, we assessed the effects of pre-treating the skin with the most widely used agonists of these TRP channels (respectively menthol, cinnamaldehyde and capsaicin) on the latencies and amplitudes of innocuous cold and noxious heat evoked potentials. Methods: A total of 64 young volunteers were recruited. Participants were assigned to one of four study groups. Each group was treated with a different a topical agonist solution (20% menthol, 10% cinnamaldehyde, 1% capsaicin, or 0.025% capsaicin) at one of the two forearms and a vehicle solution at the other forearm during a single experimental session lasting about 2 hours (approximatively 50 minutes separated the application of the first and second patch; the order of the solutions was balanced between participants). The solutions were applied using a 5x10 cm patch soaked with 2 ml of solution. The patch stayed on the skin of the subject for 20 minutes. After topical treatment of each forearm, a total of 30 high-intensity noxious heat stimuli (60°C), 30 low intensity innocuous warm stimuli (42°C) and 30 cold stimuli (10°C) were delivered to the treated skin in a pseudo random order, using a contact thermal stimulator consisting in 15 Peltier elements (each 7.7 mm²) organized onto a 3 cm diameter surface (TCS II.1, probe T03). Target temperature was reached at a rate of 300°C/s. Stimulus duration was 200 ms. The stimulator was slightly displaced within the treated area after each stimulus. Inter-stimulus interval was approximately 12 s. The EEG signal was recorded using 32 electrodes (sampling rate: 1000 Hz; average reference). Impedance was below 10 k? at each electrode. Average waveforms per experimental conditions and subjects were computed. Latencies and amplitude of the negative-positive vertex potential (N2-P2) were estimated at electrode Cz. Results: Innocuous cold (10°C) and heat (60°C) stimuli elicited clear cold-evoked potentials (CEP) and heat-evoked potentials (HEP), with latencies compatible with the conduction velocity of thinly-myelinated A-delta fibers. N2 and P2 latencies and N2-P2 peak-to-peak amplitudes were compared using Bayesian non-parametric paired sample t-tests (JASP). Menthol increased the latency and decreased the amplitude of both CEPs and HEPs. Capsaicin 1% had no effect on CEP latency but increased the latency of HEPs. Capsaicin 1% also decreased the amplitude of both CEPs and HEPs. Capsaicin 0.025% capsaicin had no effect on CEPs and HEPs. Finally, cinnamic aldehyde 10% had no effect on CEPs, but clearly increased the latency and decreased the amplitude of HEPs. Conclusions: Our results showing that menthol increases CEP latencies supports an involvement of TRPM8 in innocuous cold transduction by cold-sensitive A-delta fibers. Similarly, the finding that both capsaicin and cinnamaldehyde increase the latencies of HEPs is compatible with an involvement of TRPV1 and TRPA1 in noxious heat transduction by A-fiber nociceptors. The increased latency of HEPs after menthol could be related to previous findings suggesting that menthol may modulate TRPV1. Finally, the effects of the agonists on CEP and HEP amplitudes should be interpreted cautiously because the N2-P2 complex is dependent on stimulus saliency, which could be reduced by the ongoing thermal sensations produced by the topical treatments.
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Courtin, A., & Mouraux, A. (2021). Combining topical agonists with the recording of event-related brain potentials to probe the functional involvement of TRPM8, TRPA1 and TRPV1 in heat and cold transduction in the human skin. IASP 2021 Virtual World Congress on Pain. https://hdl.handle.net/2078.5/269257