Chronic-pain is a debilitating illness that has become exceedingly widespread with currently limited treatments. Differences in the molecular signature of nociceptors, have been demonstrated between human and the commonly-used mouse model, suggesting functional differences in detection and transmission of noxious-stimuli. Therefore, direct understanding of pain-physiology in humans is required for pain treatment. This could be facilitated by studying humans carrying deleterious genetic mutations affecting pain sensation. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with several body-functions, in particular, noxious-heat detection and inflammatory-pain. Reports of adverse effects in human trials have hinder the clinical development of TRPV1 antagonists as novel pain relievers. Hence, studies on the functional roles of TRPV1, which currently rely mainly on evidences obtained from rodents, should be extended to humans. Here, we examined humans carrying a unique missense mutation in TRPV1, rendering the channel non-functional. The affected individual demonstrated lack of aversion towards capsaicin and elevated heat-pain threshold. Surprisingly, he showed elevated cold-pain threshold and extensive neurogenic inflammatory flare and pain-responses following application of the TRPA1 channel-activator, mustard-oil. Our study provides the first direct evidence for pain-related functional-changes linked to TRPV1 in humans, which is a prime target in the development of novel pain-relievers.
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