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

Weyer-Menkhoff, Iris, MSc*; Lötsch, Jörn, MD, PhD*,†

doi: 10.1097/AJP.0000000000000677
Original Articles

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.

*Institute of Clinical Pharmacology, Goethe-University

Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Frankfurt am Main, Germany

Supported by the Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation—Pharma (TRIP, J.L.), and by the Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz (LOEWE), LOEWE-Zentrum für Translationale Medizin und Pharmakologie (J.L.). The funders had no role in method design, data selection and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflict of interest.

Reprints: Jörn Lötsch, MD, PhD, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany (e-mail:

Received September 18, 2018

Received in revised form November 21, 2018

Accepted November 27, 2018

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