Figure 7.
Kv7 channel modulators XE991 and retigabine have opposite effects on cold sensing in CMC fibers. A, Original recording showing instantaneous discharge rates in response to cooling and XE991 application. XE991 10 μm produced sensitization to cold in camphor-sensitive CMC fibers. Interstimulus interval and drug wash-in was 4 min. Lower trace, Time course of cold stimulus and temperature thresholds of activation. B, Cold-sensitizing effect of subsequently applied 10 and 100 μm XE991 shown as an increase in magnitude of the cold response. XE991 10 μm increased the cold response by 2.7-fold, and 100 μm by 2.9-fold (n = 7, p = 0.06, t test). Camphor, applied after washout of XE991, increased the cold response by 4.2-fold over baseline (mean of n = 5 CMC fibers), which was significantly more than XE991 (vs 10 μm, p = 0.002; vs 100 μm, p = 0.03, t test). Block of KV7-channels by XE991 may explain ∼64–69% of the cold sensitization of camphor. C, Sensitization to cold by XE991 did not entail a decrease in temperature threshold (control, 16.0 ± 1.7°C; XE991, 18.0 ± 1.4°C (10 μm), 21.4 ± 1.2°C (100 μm); camphor, 22.8 ± 2.0°C; n = 8/8/7/5; *p = 0.02, t test). D, Original recording showing instantaneous discharge rates in response to cooling and combined application of menthol (50 μm) and retigabine or XE991. Interstimulus interval and drug wash-in was 4 min. Lower trace, Time course of cold stimulus and temperature thresholds of activation. E, Addition of 50 μm retigabine reversed menthol-induced cold sensitization in CMC fibers (reduction by 51%), while the addition of XE991 restored and further boosted the menthol effect (increase by 33%; n = 4–5; p < 0.007, t test); in contrast, repeated cold stimulation in the presence of menthol alone showed a progressive decline of the menthol-sensitized cold response by 15%, 21%, and 23%, respectively (n = 4; p > 0.05, t test). Error bars represent SEM.