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. 2013 Oct 16;33(42):16627–16641. doi: 10.1523/JNEUROSCI.1473-13.2013

Figure 2.

Figure 2.

Cold sensitization by camphor overlaps with sensitivity to menthol. A, Original recording from a temperature-insensitive nociceptor showing instantaneous discharge rates in response to menthol application and cooling. Menthol produced de novo, partly reversible, reproducible, and concentration-dependent sensitization to cold. Interstimulus interval and drug wash-in was 5 min. Lower trace, Time course of cold stimulus and temperature thresholds of activation. B, Four-way distribution describing the percentage of mechanosensitive C-fibers of each subclass sensitized to cold by menthol (CM, temperature-insensitive nociceptor, n = 3/5; CMC, cold nociceptor, n = 3/5; CMCH, multimodal nociceptor, n = 1/9; CMH, polymodal nociceptor, n = 1/5; all, n = 8/24; red area: fibers sensitized to cold by camphor projected from Figure 1B). C, Averaged histogram (1 s bins, three-point adjacent averaging) comparing cold-sensitizing effects of menthol (closed blue circles, 50 μm; open blue circles, 500 μm) and camphor (red closed circles, pooled data from both genotypes in Fig. 1F); control. Note that a higher concentration of menthol leads to greater dynamic activation and inactivation (adaptation) by cooling. Inset, Stimulus response diagram (APs/°C) for the first linear 7.5 s of the cold stimulus (1.5°C/s, corresponding to the time interval defined by dotted lines in lower trace). The difference between both menthol concentrations was significant during the falling phase of temperature (asterisks represent p < 0.04, Wilcoxon test). D–F, Quantification of menthol sensitization to cold: increase in response magnitude (control, 4.4 ± 2.0; 50 μm, 38.1 ± 6.3; 500 μm, 71.3 ± 15.5; n = 8/8/7; p = 0.01 and p = 0.09, Wilcoxon test; D) and in peak firing frequency (control, 0.7 ± 0.4; 50 μm, 5.0 ± 1.1; 500 μm, 14.1 ± 2.8 spikes/s; n = 8/8/7; p = 0.01 and p = 0.02, Wilcoxon test; E), and a rise in threshold temperature (control, 14.4 ± 1.5°C; 50 μm, 23.2 ± 1.6°C; 500 μm, 26.1 ± 1.6°C; n = 8/8/7; p = 0.03 and p = 0.09, respectively, Wilcoxon test; F). Solid symbols represent the mean. Note that camphor 2 mm and menthol 50 μm produce equipotent cold-sensitizing effects in all three measures of sensitization (red projections in D–F represent pooled data from both genotypes shown in Fig. 1C–E).