Consequences of a Human TRPA1 Genetic Variant on the Perception of Nociceptive and Olfactory Stimuli

BackgroundTRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity.MethodsOlfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G>A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2).ResultsAmong the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2) were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049). Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.1±1.5 versus 12.3±1.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2±13.2 versus 21±12.8 mm VAS, p = 0.006), which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced.ConclusionsThe findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.背景：TRPA1离子通道（TRPA1 ion channels）参与痛觉感知（nociception），同时可被刺激性气味物质激活。基于已报道的TRPA1基因变异与热痛刺激敏感性升高的关联，本研究提出假说：该变异与嗅觉敏感性升高亦存在相关性。 方法：对比分析TRPA1变异rs11988795 G>A（该变异已被证实可增强冷痛感知）的携带者（n=38）与非携带者（n=43）的嗅觉功能与痛觉感知水平。嗅觉功能通过评估气味阈值、气味辨别能力与气味识别能力，并经鼻腔给予200ms脉冲式硫化氢（H2S）进行量化检测。痛觉感知则通过测量实验性痛觉刺激（钝性压力、电刺激、冷/热刺激，以及200ms鼻腔脉冲式二氧化碳（CO2））的痛阈值进行评估。 结果：在11名中度嗅觉减退（hyposmia）受试者中，次要等位基因A的携带者（n=2）占比偏低（70名嗅觉正常（normosmic）受试者中共有34名携带者，p=0.049）。此外，A等位基因携带者的气味辨别能力显著优于非携带者（正确辨别数分别为13.1±1.5与12.3±1.6），且报告的H2S刺激强度更高（视觉模拟评分法（Visual Analogue Scale, VAS）得分分别为29.2±13.2与21±12.8 mm，p=0.006），但无法排除刺激过程中存在三叉神经（trigeminal）成分参与的可能性。最终，本研究成功复现了“热痛刺激敏感性升高”这一既往关联结果。 结论：本研究结果与此前“人类TRPA1变异与痛觉参数存在关联”的结论相符，并将该关联拓展至气味感知领域。不过，该关联主要针对涉及三叉神经成分的刺激物，纯嗅觉效应仍存在争议。尽管如此，研究结果提示，未来靶向TRPA1的调控药物或可改变气味感知能力。