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

Stefan Schwarz, Wolfgang Greffrath, Dietrich Büsselberg* and Rolf-Detlef Treede

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 Ca²⁺ (buffered with 10 mM EGTA) inactivation (by 53 ± 6 %) and tachyphylaxis (by 42 ± 7 % across three stimuli) were still observed (n = 8). The same was true when intracellular Ca²⁺ was buffered by 10 mM 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 Ca²⁺.

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.

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