Changes in excitability indices of cutaneous afferents produced by ischaemia in human subjects

Abstract

Relatively brief periods of ischaemia paralyse the electrogenic Na¤-K¤ pump, increase [K¤]ï and produce membrane depolarization. In sensory axons, the axonal depolarization can lead to hyperexcitability sufficient to result in ectopic activity. This is less likely in motor axons, probably because the former express a threshold conductance, thought to be mediated by persistent Na¤ channels (Bostock & Rothwell, 1997). Following release of ischaemic compression, heightened activity of the electrogenic Na¤-K¤ pump leads to axonal hyperpolarization. Paradoxically, ectopic activity can then be quite intense, particularly in sensory axons, and this is probably due, in part, to activation of an inwardly rectifying conductance that is again expressed more on sensory axons than on motor axons ).The changes in axonal excitability during ischaemia and after its release can be reproduced reasonably well by longlasting depolarizing and hyperpolarizing currents (Baker & Bostock, 1989), suggesting that the change in membrane potential is largely sufficient to explain some of the effects of ischaemia. However, it is likely that there is more to the excitability changes produced by ischaemia than the change in membrane potential. In a short communication on voltageclamped rat axons, Brismar (1981) reported that anoxia decreased maximal Na¤ permeability and shifted the relationship between Na¤ channel inactivation and membrane potential to more negative potentials, so that more Na¤ channels were inactivated at rest. In addition, ischaemia can have complex effects, both direct and indirect, on other 1. The present study was undertaken to determine whether mechanisms other than membrane depolarization contribute to the changes in excitability of cutaneous afferents of the median nerve under ischaemic conditions. 2. In six healthy subjects, axonal excitability was measured as the reciprocal of the threshold for a compound sensory action potential (CSAP) of 50% maximal amplitude. Refractoriness and supernormality were measured as threshold changes 2 and 7 ms, respectively, after supramaximal conditioning stimuli. The strength-duration time constant (ôSD) was calculated from the thresholds for unconditioned CSAPs using test stimuli of 0·1 and 1·0 ms duration. Changes in these indices were measured when subthreshold polarizing currents lasting 10 or 100 ms were applied, before, during and after ischaemia for 13 min. 3. At rest, the change in supernormality produced by polarizing currents was greater with the longer polarizing current, indicating that it took up to 100 ms to charge the internodal capacitance. 4. Refractoriness and its dependence on excitability increased more than expected during ischaemia. Supernormality was abolished during ischaemia, and reached a maximum after ischaemia but was then barely altered by polarizing current. ôSD had a similar relationship to excitability before, during and after ischaemia. 5. By contrast, during continuous depolarizing current for 8 min to mimic the depolarization produced by ischaemia, ...

Local Antinociception Induced by Endothelin-1 in the Hairy Skin of the Rat's Back

“…Although we have no direct evidence of conduction block from ischemia in these studies, others have shown that ischemia of peripheral nerve leads to increased neuronal accommodation5 and slowing of conduction and lengthening of the refractory period26, all three being indicators of reduced axonal excitability. These changes in conduction parameters were made in large myelinated axons, and it was determined that prolonged membrane depolarization could not alone account for the conduction defects, suggesting that some neuroactive substance or metabolic shift had a direct effect on Na + channel inactivation48.…”

Why Are Sensory Axons More Vulnerable for Ischemia than Motor Axons?

“…The continuous increase in 50% refractory period during ischemia is consistent with gradually developing transient Na + current inactivation due to continuing depolarization [10], [24]. For 50% refractory period these changes were more prominent in sensory axons, again indicating faster inactivation of transient Na + channels in sensory than motor axons due to more prominent depolarization.…”

Differences in responses of cutaneous afferents in the human median and sural nerves to ischemia

“…Threshold often provides a reasonable indication of membrane potential, but does so less accurately during prolonged ischemia when inactivation (± blockage) of Na + channels becomes an important determinant of axonal excitability. 1,9 Nevertheless, threshold can still be used to determine whether the lesser changes in refractoriness, supernormality, and SD for sural afferents were appropriate for the lesser threshold decrease for that nerve. Figure 3A illustrates the relationship between SD and threshold during ischemia (left) and its release (right) for cutaneous afferents in the two nerves.…”

“…With the more extreme depolarization, there was evidence for "accommodation" in the threshold for median afferents, as might be expected if the change in excitability was limited by Na + channel inactivation 1 or Na + channel blockade. 9 In the right panels of Figure 3, the curved arrows indicate the sequence for the complex postischemic threshold change of the median afferents. Despite this complex threshold trajectory, the relationships between SD , refractoriness, supernormality, and threshold were again similar during hyperpolarizing threshold changes for the two nerves (apart from the baseline difference in SD ).…”

“…The changes in excitability of median afferents during ischemia and its release have been well-documented in previous studies from this laboratory using threshold tracking. 3,9,17 Ischemia paralyzes the Na + /K + pump and this leads to axonal depolarization as K + ions accumulate outside the axon, and Na + ions inside. With the release of Abbreviations: CSAP, compound sensory action potential; I H , the hyperpolarization-activated cation conductance responsible for inward rectification; SD , strength-duration time constant…”