NaV1.7 and pain: contribution of peripheral nerves

The sodium channel NaV1.7 contributes to action potential generation and propagation. Loss-of-function mutations in patients lead to congenital indifference to pain, though it remains unclear where on the way from sensory terminals to CNS the signalling is disrupted. We confirm that conditional deletion of NaV1.7 in advillin expressing sensory neurons leads to impaired heat and mechanical nociception in behavioural tests. With single-fiber recordings from isolated skin we found (1) a significantly lower prevalence of heat responsiveness to in normally mechanosensitive C-fibers, although (2) the rare heat responses appeared quite vigorous and (3) heat-induced CGRP release was normal. In biophysical respects, while electrical excitability, rheobase and chronaxy were normal (4) axonal conduction velocity was 20% slower than in congenic wildtype mice (5) and when challenged with double pulses (< 100 ms interval), the second action potential showed more pronounced latency increase (6). Upon prolonged electrical stimulation at 2 Hz, (7) activity-dependent slowing of nerve fiber conduction was markedly less and (8) was less likely to result in conduction failure of the mutant single-fibers. Finally, recording of compound action potentials from the whole saphenous nerve confirmed slower conduction and less activity-dependent slowing as well as the functional absence of a large subpopulation of C-fibers (9) in conditional Nav1.7 knock-outs. In conclusion, the clear deficits in somatic primary afferent functions shown in our study may be complemented by previously reported synaptic dysfunction and opioidergic inhibition, together accounting for the complete insensitivity to pain in the human mutants lacking Nav1.7

Angiotensin II facilitates sympathetic transmission in rat hind limb circulation

We developed a novel method to stimulate the sympathetic innervation of the isolated, perfused rat hind limb to investigate whether a subpressor concentration of angiotensin II (Ang II) facilitates noradrenergic transmission in the vascular bed to skeletal muscle. We electrically stimulated the lumbar sympathetic trunk while perfusing the preparation with artificial medium. Seventy-five percent of the resulting frequency-dependent increases in perfusion pressure were mediated by alpha 1-adrenergic receptors. Ang II (10 nM) significantly enhanced the effects of nerve stimulation at 1 and 10 Hz (by 42% and 35%, respectively). At a supramaximal stimulation frequency (20 Hz), Ang II prolonged the duration of the response without changing the peak increase in pressure. The reuptake inhibitor cocaine did not influence the effects of Ang II at 1 and 10 Hz but blocked the effect at 20 Hz. To control for nonspecific synergism with norepinephrine, we compared Ang II with vasopressin. Both peptides potentiated the pressor response to exogenous norepinephrine; however, vasopressin did not change the pressor response to nerve stimulation at any frequency. We conclude that Ang II, but not vasopressin, facilitates noradrenergic transmission in skeletal muscle resistance vessels, independent of its direct vasoconstrictor activity. The neurovascular preparation we describe may be useful in addressing other hypotheses concerning sympathetic transmission in skeletal muscle resistance vessels.</jats:p