Tumbala Gutti Divya, Carr Richard, Schmelz Martin, Rukwied Roman
Experimental Pain Research, MCTN, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
Eur J Pain. 2025 Feb;29(2):e4726. doi: 10.1002/ejp.4726. Epub 2024 Sep 19.
BACKGROUND: We examined de-functionalization and temporal functional recovery of C-nociceptor evoked pain after topical 8% capsaicin applied for 4 consecutive days. METHODS: Capsaicin and placebo patches were applied to human forearm skin (n = 14). Cold, warmth and heat pain thresholds, pain NRS to electrical and thermal (48°C, 5 s) stimuli and axon reflex flare were recorded weekly for 49 days. Mechanical and heat sensitive ('polymodal') nociceptors were activated by single electrical half-period sinusoidal pulses (0.5 s, 1 Hz). Mechanical and heat insensitive ('silent') nociceptors were activated by 4 Hz sinusoidal stimuli. RESULTS: Capsaicin abolished heat pain. Sensation to electrical sinusoidal stimulation was reduced but never abolished during the treatment. Pain to electrical 1 Hz 'polymodal' nociceptor stimulation took longer to recover than pain ratings to 4 Hz 2.5 s sinusoidal stimulation activating 'polymodal' and 'silent' nociceptors (35 vs. 21 days). Heat pain was indifferent to placebo from day 21-49. Axon reflex flare was abolished during capsaicin and only recovered to ~50% even after 49 days. CONCLUSIONS: Capsaicin abolishes heat transduction at terminal nociceptive endings, whereas small-diameter axons sensitive to sinusoidal electrical stimulation can still be activated. 1 Hz depolarizing stimuli evoke burst discharges, as demonstrated before, and recover slower after capsaicin than single pulses induced by 4 Hz. The difference in recovery suggests differential time course of functional regeneration for C-nociceptor sub-types after capsaicin. All sensations recovered completely within 7 weeks in healthy subjects. Our findings contrast analgesia lasting for months in spontaneous neuropathic pain patients treated with 8% capsaicin. SIGNIFICANCE: Sinusoidal electrical stimulation can still activate small diameter axons desensitized to heat after 4 consecutive days of topical 8% capsaicin application and reveals differential temporal functional regeneration of C-nociceptor sub-types. Electrical sinusoidal stimulation may detect such axons that no longer respond to heat stimuli in neuropathic skin.
背景：我们研究了连续4天局部应用8%辣椒素后C类伤害感受器诱发疼痛的失功能化及时间性功能恢复情况。 方法：将辣椒素贴片和安慰剂贴片应用于人体前臂皮肤（n = 14）。每周记录49天的冷、温、热痛阈值、对电刺激和热刺激（48°C，5秒）的疼痛数字评分量表（NRS）以及轴突反射性潮红。通过单个电半周期正弦脉冲（0.5秒，1赫兹）激活机械和热敏感（“多模式”）伤害感受器。通过4赫兹正弦刺激激活机械和热不敏感（“沉默”）伤害感受器。 结果：辣椒素消除了热痛。在治疗期间，对电正弦刺激的感觉有所降低，但从未完全消除。对1赫兹“多模式”伤害感受器刺激的疼痛恢复时间比对4赫兹2.5秒正弦刺激激活“多模式”和“沉默”伤害感受器的疼痛评分恢复时间更长（35天对21天）。从第21天到49天，热痛对安慰剂无反应。轴突反射性潮红在辣椒素治疗期间消失，即使在49天后也仅恢复到约50%。 结论：辣椒素消除了伤害性感受器末梢的热传导，而对正弦电刺激敏感 的小直径轴突仍可被激活。如前所示，1赫兹去极化刺激会诱发爆发性放电，且辣椒素处理后其恢复比4赫兹诱导的单个脉冲更慢。恢复的差异表明辣椒素处理后C类伤害感受器亚型的功能再生时间进程不同。在健康受试者中所有感觉在7周内完全恢复。我们的研究结果与用8%辣椒素治疗自发神经性疼痛患者时持续数月 的镇痛效果形成对比。 意义：连续4天局部应用8%辣椒素后对热脱敏的小直径轴突仍可被正弦电刺激激活，这揭示了C类伤害感受器亚型不同的时间性功能再生情况。正弦电刺激可能检测到神经性皮肤中不再对热刺激产生反应的此类轴突。
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