TRPA1 Sensitization Produces Hyperalgesia to Heat but not to Cold Stimuli in Human Volunteers

Abstract

Background: Transient receptor potential ion channels play a role in thermal hyperalgesia and are among targets of novel analgesics. However, a role of TRPA1 in either heat or cold hyperalgesia is controversial. In this study, changes in thermal sensitivity were assessed following topical application of a specific sensitizer of TRPA1 and compared with the effects of sensitizers of TRPV1 and TRPM8. Methods: Employing a randomized cross-over design, thermal thresholds were assessed in 16 pain-free volunteers before and at 20 minutes after topical application of cinnamaldehyde, capsaicin or menthol stimulating TRPA1, TRPV1, or TRPM8, respectively. Cold or warm detection thresholds and cold or heat pain thresholds were assessed according to the standardized quantitative sensory testing protocol proposed by the German Research Network on Neuropathic Pain. Results: The effects of different irritants displayed a cluster structure. Hyperalgesia was induced by capsaicin and cinnamaldehyde on heat pain thresholds and by menthol on cold pain thresholds (Cohen d=2.2035, 0.9932, and 1.256, respectively). A second cluster comprised large effects directed toward hyposensitization, such as cold hyposensitization induced by capsaicin and cinnamaldehyde, or small or absent hyposensitizing effects. Conclusions: The observation that the TRPA1 irritant cinnamaldehyde induced heat hyperalgesia at an effect sizes comparable with that of capsaicin attributes TRPA1 a role in human heat-induced pain. Results suggest the inclusion of heat pain as a major efficacy measure in human experimental studies of the effects of TRPA1 antagonists and the development of TRPA1 antagonists for clinical pain settings involving heat hyperalgesia.

Interpretation of cluster structures in pain‐related phenotype data using explainable artificial intelligence (XAI)

“…Relevant for the subgrouping were the pain thresholds for heat and cold stimuli and additionally the individual pain thresholds for cold stimuli applied to sensitized skin. An effect of topical capsaicin sensitization on the perception of cold stimuli reproduces an observation recently made in the same laboratory (Weyer‐Menkhoff & Lotsch, 2019) and in independent research units (Callsen et al., 2008; Mohr et al., 2008). The two‐cluster solution separated the subjects according to either high (cluster #1) or low (cluster #2) pain sensitivity.…”

Human surrogate models of central sensitization: A critical review and practical guide

“…TRPA1 receptors are activated at low temperatures close to cold pain (<17°C) but also by topical application of natural oils such as cinnamaldehyde and mustard oil (Bandell et al., 2004 ). The specificity of these receptors for cold stimuli remains debated (Weyer‐Menkhoff & Lötsch, 2018 , 2019 ), as they have been also implicated in the perception of heat (e.g. Moparthi et al., 2016 ).…”

Childhood traumatization is associated with differences in TRPA1 promoter methylation in female patients with multisomatoform disorder with pain as the leading bodily symptom

“…TRPA1 may also be involved in mechanosensation [18–22], neurogenic inflammation, central sensitization, microglia activation, and transition from acute to chronic pain [18, 20, 21, 23–25]. In human trials, TRPA1 agonists applied to the skin indeed induce mechanical hypersensitivity [26] and heat hyperalgesia [26, 27].…”