Electrophysiological evidence for tetrodotoxin-resistant sodium channels in slowly conducting dural sensory fibers.

A tetrodotoxin (TTX)-resistant sodium channel was recently identified that is expressed only in small diameter neurons of peripheral sensory ganglia. The peripheral axons of sensory neurons appear to lack this channel, but its presence has not been investigated in peripheral nerve endings, the site of sensory transduction in vivo. We investigated the effect of TTX on mechanoresponsiveness in nerve endings of sensory neurons that innervate the intracranial dura. Because the degree of TTX resistance of axonal branches could potentially be affected by factors other than channel subtype, the neurons were also tested for sensitivity to lidocaine, which blocks both TTX-sensitive and TTX-resistant sodium channels. Single-unit activity was recorded from dural afferent neurons in the trigeminal ganglion of urethan-anesthetized rats. Response thresholds to mechanical stimulation of the dura were determined with von Frey monofilaments while exposing the dura to progressively increasing concentrations of TTX or lidocaine. Neurons with slowly conducting axons were relatively resistant to TTX. Application of 1 microM TTX produced complete suppression of mechanoresponsiveness in all (11/11) fast A-delta units [conduction velocity (c.v.) 5-18 m/s] but only 50% (5/10) of slow A-delta units (1.5 <c.v.<5 m/s) and 13% (2/15) of C units (c.v. </=1.5 m/s). The mean TTX concentration that produced complete suppression of mechanoresponsiveness was approximately 270-fold higher in C units than in fast A-delta units. In contrast, no significant difference was found between C and A-delta units in the concentration of lidocaine required for complete suppression of mechanoresponsiveness, indicating that the greater TTX resistance of mechanoresponsiveness in C units is not attributable to differences in safety factor unrelated to channel subtype. These data offer indirect evidence that a TTX-resistant channel subtype is expressed in the terminal axonal branches of many of the more slowly conducting (C and slow A-delta) dural afferents. The channel appears to be present in these fibers, but not in the faster A-delta fibers, in sufficient numbers to support the initiation and propagation of mechanically induced impulses. Comparison with previous data on the absence of TTX resistance in peripheral nerve fibers suggests that the TTX-resistant sodium channel may be a distinctive feature of the receptive rather than the conductive portion of the sensory neuron's axonal membrane.