The TRPA1 and TRPV1 receptors are important pharmaceutical targets for antipruritic and analgesic therapy. Obtaining further knowledge on their roles and interrelationship in humans is therefore crucial. Preclinical results are contradictory concerning coexpression and functional interdependency of TRPV1 and TRPA1, but no human evidence exists. This human experimental study investigated whether functional responses from the subpopulation of TRPA1+ nociceptors could be evoked after defunctionalization of TRPV1+ nociceptors by cutaneous application of high-concentration capsaicin. Two quadratic areas on each forearm were randomized to pretreatment with an 8% topical capsaicin patch or vehicle for 24 hours. Subsequently, areas were provoked by transdermal 1% topical capsaicin (TRPV1 agonist) or 10% topical allyl isothiocyanate (“AITC,” a TRPA1 agonist), delivered by 12 mm Finn chambers. Evoked pain intensities were recorded during pretreatments and chemical provocations. Quantitative sensory tests were performed before and after provocations to assess changes of heat pain sensitivity. Imaging of vasomotor responses was used to assess neurogenic inflammation after the chemical provocations. In the capsaicin-pretreated areas, both the subsequent 1% capsaicin- and 10% AITC-provoked pain was inhibited by 92.9 ± 2.5% and 86.9 ± 5.0% (both: P < 0.001), respectively. The capsaicin-ablated skin areas showed significant heat hypoalgesia at baseline (P < 0.001) as well as heat antihyperalgesia, and inhibition of neurogenic inflammation evoked by both 1% capsaicin and 10% AITC provocations (both: P < 0.001). Ablation of cutaneous capsaicin-sensitive afferents caused consistent and equal inhibition of both TRPV1- and TRPA1-provoked responses assessed psychophysically and by imaging of vasomotor responses. This study suggests that TRPA1 nociceptive responses in human skin strongly depend on intact capsaicin-sensitive, TRPV1+ fibers.
TRPA1 and TRPV1 are crucial nociceptive transducers. Using capsaicin ablation in human skin we reveal that TRPA1-induced pain responses depend on intact capsaicin-sensitive fibers, signifying substantial functional TRPA1–TRPV1 overlap.
aLaboratory of Experimental Cutaneous Pain and Itch Research, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
bDepartment of Clinical Medicine, Faculty of Medicine, Aalborg University, Aalborg, Denmark
Corresponding author. Address: SMI, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Fredrik Bajers Vej 7A, A2-203, DK—9220 Aalborg E, Denmark. Tel.: +45 24 46 45 15. E-mail address: email@example.com (H.H. Andersen).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received January 16, 2018
Received in revised form May 02, 2018
Accepted May 22, 2018