Inactivation and tachyphylaxis of heat‐evoked inward currents in nociceptive primary sensory neurones of rats

1 Membrane currents evoked by repeated noxious heat stimuli (43–47 °C) of 3 s duration were investigated in acutely dissociated dorsal root ganglion (DRG) neurones of adult rats. The heat stimuli generated by a fast solution exchanger had a rise time of 114 ± 6 ms and a fall time of 146 ± 13 ms. 2 When heat stimuli were applied to heat‐sensitive small (≤ 32·5 μm) DRG neurones, an inward membrane current ( I heat ) with a mean peak of 2430 ± 550 pA was observed ( n = 19 ). This current started to activate and deactivate with no significant latency with respect to the heat stimulus. The peak of I heat was reached with a rise time of 625 ± 115 ms. When the heat stimulus was switched off I heat deactivated with a fall time of 263 ± 17 ms. 3 During constant heat stimulation I heat decreased with time constants of 4–5 s (inactivation). At the end of a 3 s heat stimulus the peak current was reduced by 44 ± 5 % ( n = 19 ). 4 Current‐voltage curves revealed outward rectifying properties of I heat and a reversal potential of −6·3 ± 2·2 mV ( n = 6 ). Inactivation was observed at all membrane potentials investigated (−80 to 60 mV); however, inactivation was more pronounced for inward currents (37 ± 5 %) than for outward currents (23 ± 6 %, P < 0 ·05). 5 When neurones were investigated with repeated heat stimuli (3 to 5 times) of the same temperature, the peak current relative to the first I heat declined by 48 ± 6 % at the 3rd stimulus ( n = 19 ) and by 54 ± 18 % at the 5th stimulus ( n = 4 ; tachyphylaxis). 6 In the absence of extracellular Ca 2+ (buffered with 10 m m EGTA) inactivation (by 53 ± 6 %) and tachyphylaxis (by 42 ± 7 % across three stimuli) were still observed ( n = 8 ). The same was true when intracellular Ca 2+ was buffered by 10 m m BAPTA (inactivation by 49 ± 4 %, tachyphylaxis by 52 ± 7 % across three stimuli; n = 13 ). Thus, inactivation and tachyphylaxis were mainly independent of intra‐ and extracellular Ca 2+ . 7 These results indicate that inactivation and tachyphylaxis of heat‐evoked inward currents can be observed in vitro , similar to adaptation and suppression of action potential discharges elicited by comparably fast heat stimuli in vivo. Whereas the voltage dependence of I heat resembles that of capsaicin‐induced membrane currents ( I Caps ), the independence of inactivation and tachyphylaxis of I heat from calcium is in clear contrast to I Caps . A similar difference in calcium dependence of inactivation has been reported between heat‐evoked and capsaicin‐induced currents through the cloned capsaicin receptor channel VR1. Thus, the properties of I heat and of VR1 largely account for the adaptation and suppression of heat‐evoked nociceptor discharges.