Figure 4.

Camphor and menthol sensitize to cold via independent mechanisms. A–D, Camphor (2 mm)-induced sensitization to cooling is increased by subsequent coapplication of menthol (50 μm). A, Original recording from a temperature-insensitive nociceptor (CM) showing instantaneous discharge rates in response to cooling after application of camphor (2 mm) and an equipotent dose of menthol (50 μm). Lower trace, Time course of cold stimulus and threshold temperature of activation. B–D, Quantification of the synergistic effect of menthol on the camphor-induced cold sensitization: increase in response magnitude (82.1 ± 18.3–102.2 ± 18.5; p = 0.028, Wilcoxon test; B); increase in peak discharge (10.0 ± 2.4–16.6 ± 4.0 spikes/s, p = 0.028, Wilcoxon test; C); and rise in temperature threshold (22.1 ± 1.6°C–25.2°C±1.3; p = 0.046, Wilcoxon test; D). Bold dotted lines: average of n = 10, dotted arrow: representative sample shown in A. E–H, Cold sensitization induced by a saturating dose of menthol is further increased by coapplication of camphor (2 mm). E, Original recording from a cold nociceptor showing instantaneous discharge rates in response to cooling after application of menthol (500 μm) and camphor (2 mm). Lower trace, Time course of cold stimulus and threshold temperature of activation. F–H, Quantification of the synergistic effect of camphor on the menthol-induced cold sensitization: increase in response magnitude (71.8 ± 19.6–92.1 ± 24.1; p = 0.1, Wilcoxon test; F) and peak discharge (13.8 ± 3.3–22.7 ± 4.9 spikes/s, p = 0.04, Wilcoxon test; G), and rise in temperature threshold (27.4 ± 1.1°C–29.3 ± 0.4°C; p = 0.1, Wilcoxon test; H). Bold dotted lines, Average of n = 6; dotted arrow, representative sample shown in E.