SUMMARY1. The nature, distribution and function of rectifying channels in rat spinal root myelinated axons has been assessed with selective blocking agents and a variety of intracellular and extracellular recording techniques.2. The electrotonic responses of roots poisoned with tetrodotoxin (TTX) to constant current pulses had fast (rise time << 1 ms) and slow components, which were interpreted in terms of Barrett & Barrett 's (1982) revised cable model for myelinated nerve. Depolarization evoked a rapid outward rectification (time constant, T -.0 5 ms), selectively blocked by 4-aminopyridine (4AP, 1 mM), and a slow outward rectification (,r-15 ms), selectively blocked by tetraethylammonium (TEA, 1 mM) or Ba2+ (0-5 mM). Hyperpolarization evoked an even slower inward rectification, selectively blocked by Cs+ (3 mM) but not by Ba2 .3. From the different effects of the blocking agents on the fast and slow components of electrotonus, it was deduced (a) that the inward rectification is a property of the internodal axon, (b) that the slow outward rectifier is present at the nodes, and probably the internodes as well, and (c) that the 4AP-sensitive channels have a minor nodal and a major internodal representation.4. TEA and Ba2+ reduced the accommodation of roots and fibres not poisoned with TTX to long current pulses, whereas 4AP facilitated short bursts of impulses in response to a single brief stimulus.5. TEA and Ba2+ also abolished a late hyperpolarizing after-potential (peaking at 20-80 ms), while 4AP enhanced the depolarizing after-potential in normal fibres, and abolished an early hyperpolarizing after-potential (peaking at 1-3 ms) in depolarized fibres. Corresponding to the later after-potentials were post-spike changes in excitability and conduction velocity, which were affected similarly by the blocking agents. Cs+ increased the post-tetanic depression attributable to electrogenic hyperpolarization.6. The physiological roles of the three different rectifying conductances are discussed. It is also argued that the prominent ohmic 'leak conductance', usually ascribed to the nodal axon, must arise in an extracellular pathway in series with the rectifying internodal axon.

SUMMARY1. Double-barrelled ion-sensitive micro-electrodes were used to measure changes in the intracellular activities of K+, Na+ and Cl-(aK, aNa, acl) in glial cells of slices from guinea-pig olfactory cortex during repetitive stimulation of the lateral olfactory tract.2. Base-line levels of aj , aia and ai1 were about 66, 25 and 6 mm, respectively, for cells with resting potentials higher than -80 mV. During stimulation, intraglial aj and ai1 increased, whereas aia decreased. Within about 2 min after stimulation the ion activities returned to their base-line levels.3. The Cl-equilibrium potential was found to be close to the membrane potential (Em). There was also a strong correlation between changes of Em and aC1. These observations indicate a high Cl-conductance of the glial cell membrane. 4. In the presence of Ba2+, the usual depolarizing response of the glial cells to a rise of the extracellular K+ activity (a4) reversed into a membrane hyperpolarization. Furthermore, Ba2+ strongly reduced the stimulus-related rise of intraglial a4. An additional application of ouabain blocked both the membrane hyperpolarization as well as the remaining rise of a.5. In conclusion, our data show that glial cells in guinea-pig olfactory cortex slices possess at least two mechanisms of K+ accumulation. One mechanism is sensitive to the K+ channel blocker Ba2+ and might be a passive KCl influx. The other appears to be the electrogenic Na+/K+ pump, which can be activated by excess extracellular K+.

SUMMARY1. Myelinated nerve fibres with a reduced safety factor for conduction due to demyelination are easily blocked by trains of impulses. To find out why, in vivo recordings from rat ventral root fibres demyelinated with diphtheria toxin have been supplemented with in vivo and in vitro recordings from normal fibres.2. Despite a small rise in extracellular potassium activity, normal fibres were invariably hyperpolarized by intermittent trains of impulses. This hyperpolarization resulted in an increase in threshold and also in an enhancement of the depolarizing after-potential and the superexcitable period.3. Replacement of NaCl in the extracellular solution by LiCl completely blocked both the membrane hyperpolarization and the threshold increase which were normally observed during intermittent trains of impulses. 4. At demyelinated nodes which were blocked by trains of impulses (10-50 Hz), conduction block was preceded by a rise in threshold current and an increase in internodal conduction time, but by no detectable reduction in the outward current generated by the preceding node. 5. It was found possible to prevent the threshold from changing during a train by automatic adjustment of a d.c. polarizing current. This 'threshold clamp' prevented the conduction failure and virtually abolished the changes in internodal conduction time.6. The threshold changes were attributed to hyperpolarization, as in normal fibres, since (a) the polarizing current required to prevent them was always a depolarizing current, and (b) they were accompanied by an increase in superexcitability.7. The post-tetanic depression that can follow continuous trains of impulses was attributed to the combination of increased threshold and enhanced superexcitable period due to hyperpolarization.8. It is concluded that the susceptibility of these demyelinated fibres to impulse trains is not due to a membrane depolarization induced by extracellular potassium accumulation but to a membrane hyperpolarization as a consequence of electrogenic sodium pumping.

Infusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxaliplatin neuropathy, whereas a common symptom of chronic oxaliplatin neuropathy is pain. Here we examine the role of the sodium channel isoform Na V 1.6 in mediating the symptoms of acute oxaliplatin neuropathy. Compound and single-action potential recordings from human and mouse peripheral axons showed that cooling in the presence of oxaliplatin (30-100 μM; 90 min) induced bursts of action potentials in myelinated A, but not unmyelinated C-fibers. Whole-cell patch-clamp recordings from dissociated dorsal root ganglion (DRG) neurons revealed enhanced tetrodotoxin-sensitive resurgent and persistent current amplitudes in large, but not small, diameter DRG neurons when cooled (22°C) in the presence of oxaliplatin. In DRG neurons and peripheral myelinated axons from Scn8a med/med mice, which lack functional Na V 1.6, no effect of oxaliplatin and cooling was observed. Oxaliplatin significantly slows the rate of fast inactivation at negative potentials in heterologously expressed mNa V 1.6r in ND7 cells, an effect consistent with prolonged Na V open times and increased resurgent and persistent current in native DRG neurons. This finding suggests that Na V 1.6 plays a central role in mediating acute cooling-exacerbated symptoms following oxaliplatin, and that enhanced resurgent and persistent sodium currents may provide a general mechanistic basis for cold-aggravated symptoms of neuropathy.chemotherapy | peripheral nerve | abnormal axonal excitability | repetitive action potential discharge C linical use of the highly effective chemotherapeutic oxaliplatin is compromised by an acute and a chronic form of peripheral neuropathy. Acutely, 85-90% of patients exhibit muscle fasciculations (1, 2), sensory paresthesias, and occasional dysesthesias (3), all triggered by mild cooling. Although chronic oxaliplatin-induced neuropathy has been recently linked to changes in the expression and sensitivity of transient receptor potential (TRP) channels TRPM8 and TRPA1 (4, 5), two-pore domain potassium channels (TREK1, TRAAK) and the hyperpolarization-activated channel HCN1 (6), the mechanism underlying acute oxaliplatin neuropathy remains unresolved. Several candidate mechanisms have been proposed including potassium channel blockade (7), calcium chelation (8), and alterations in voltage-gated sodium channel (Na V ) kinetics (9, 10), but none adequately account for motor and sensory symptoms nor their exacerbation by cooling.

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