Recovery from tachyphylaxis of TRPV1 coincides with recycling to the surface membrane

Significance TRPV1 ion channel plays an important role in the transmission and modulation of pain. Desensitization of TRPV1 in nociceptors is adaptable for analgesic therapy. One type of desensitization is tachyphylaxis that reflects reduced TRPV1 responses to repetitive stimuli. To understand the mechanism underlying the whole-cell tachyphylaxis, here we used an orthogonal electro-optical approach integrating electrophysiology and light-sheet microscopy. We show that the intensity of tachyphylaxis is regulated by the strength of inducing stimulation, and that TRPV1 channels undergo activity-gated recycling to regulate their surface expression level thereby the degree of tachyphylaxis. This study provides real-time insights into the establishment of tachyphylaxis and helps to understand desensitization-based analgesics.