Nociceptive TRP channels function as molecular target for several antifungal drugs

Abstract

Background/objectives: Topically applied antifungal agents can induce adverse effects, such as pain and irritation. The transient receptor potential (TRP) channels-TRPA1 and TRPV1-mainly expressed in sensory neurons, act as sensors for detecting irritants. This study aims to evaluate the involvement of nociceptive channels in topical antifungal-induced pain and irritation. We tested nine topical antifungals belonging five classes: isoconazole, econazole, miconazole, clotrimazole, and ketoconazole as imidazoles; liranaftate as a thiocarbamate; terbinafine as an allylamine; amorolfine as a morpholine; and butenafine as a benzylamine.

Methods: Intracellular calcium concentrations ([Ca²⁺]_i) and membrane currents in response to antifungals were measured to estimate channel activity using heterologously expressing cells and isolated mouse sensory neurons.

Results: In mouse TRPA1-expressing cells, all the tested drugs induced an increase in [Ca²⁺]_i, which was abrogated or reduced by a TRPA1 blocker. Although many drugs evoked the TRPA1-nonspecific [Ca²⁺]_i response at high concentrations, responses to clotrimazole, ketoconazole, and liranaftate were TRPA1 specific and elicited current responses in TRPA1-expressing cells. In mouse TRPV1-expressing cells, clotrimazole and ketoconazole elicited [Ca²⁺]_i and current responses. In mouse sensory neurons, liranaftate-induced increase in [Ca²⁺]_i was abrogated by a TRPA1 blocker and Trpa1 deletion. Responses to ketoconazole were inhibited by TRPA1 and TRPV1 blockers and by the genetic deletion of either channel.

Conclusion: These results suggest that topical antifungal-induced pain and irritation are attributable to the activation of nociceptive TRPA1 and/or TRPV1 channel/s. Consequently, caution should be exercised in the use of topical antifungals with symptoms of pain.

Keywords: Ca2+‐imaging; gene‐knockout mouse; nociceptor; sensory neuron; whole‐cell patch‐clamp.