Diphenhydramine (DPH) has been broadly used to treat allergy. When used as a topical medicine, DPH temporarily relieves itching and pain. Although transient receptor potential type A1 (TRPA1) channel is known to play roles in both acute and chronic itch and pain, whether DPH affects the activities of TRPA1 remains unclear. Using whole-cell patch clamp recordings, we demonstrated that DPH modulates the voltage-dependence of TRPA1. When co-applied with a TRPA1 agonist, DPH significantly enhanced the inward currents while suppressing the outward currents of TRPA1, converting the channel from outwardly rectifying to inwardly rectifying. This effect of DPH occurred no matter TRPA1 was activated by an electrophilic or non-electrophilic agonist and for both mouse and human TRPA1. The modulation of TRPA1 by DPH was maintained in the L906C mutant, which by itself also causes inward rectification of TRPA1, indicating that additional acting sites are present for the modulation of TRPA1 currents by DPH. Our recordings also revealed that DPH partially blocked capsaicin evoked TRPV1 currents. These data suggest that DPH may exert its therapeutic effects on itch and pain, through modulation of TRPA1 in a voltage-dependent fashion.

苯海拉明 (DPH) 已被广泛用于治疗过敏症。当用作外用药物时，DPH 可暂时缓解瘙痒和疼痛。尽管已知瞬时受体电位 A1 型 (TRPA1) 通道在急性和慢性瘙痒和疼痛中发挥作用，但 DPH 是否影响 TRPA1 的活性仍不清楚。使用全细胞膜片钳记录，我们证明 DPH 调节 TRPA1 的电压依赖性。当与 TRPA1 激动剂共同应用时，DPH 显着增强内向电流，同时抑制 TRPA1 的外向电流，将通道从外向整流转换为内向整流。无论 TRPA1 是被亲电还是非亲电激动剂激活，对于小鼠和人 TRPA1，DPH 的这种作用都会发生。DPH 对 TRPA1 的调节在 L906C 突变体中得以维持，这本身也会导致 TRPA1 的内向整流，表明存在额外的作用位点用于 DPH 调节 TRPA1 电流。我们的录音还显示 DPH 部分阻断了辣椒素诱发的 TRPV1 电流。这些数据表明，DPH 可能通过以电压依赖性方式调节 TRPA1 来发挥其对瘙痒和疼痛的治疗作用。