Journal Article

Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures

Nau, Carla, Babes, Alexandru, Leffler, Andreas, Reeh, Peter W., Cendan, Cruz Miguel, Wood, John N., Carr, Richard W., Kobayashi, Jin-ichi, Zimmermann, Katharina

2007

Overview

Sensory acuity deteriorates at cold temperatures, but pain perception persists and cold stimuli themselves can be painful. A voltage-gated sodium channel, Na v 1.8, is implicated in this perception. Unlike other channels, Na v 1.8 does not inactivate at lower temperatures and its currents are actually larger in colder conditions Sensory acuity and motor dexterity deteriorate when human limbs cool down, but pain perception persists and cold-induced pain can become excruciating 1 . Evolutionary pressure to enforce protective behaviour requires that damage-sensing neurons (nociceptors) continue to function at low temperatures. Here we show that this goal is achieved by endowing superficial endings of slowly conducting nociceptive fibres with the tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na v 1.8 (ref. 2 ). This channel is essential for sustained excitability of nociceptors when the skin is cooled. We show that cooling excitable membranes progressively enhances the voltage-dependent slow inactivation of tetrodotoxin-sensitive VGSCs. In contrast, the inactivation properties of Na v 1.8 are entirely cold-resistant. Moreover, low temperatures decrease the activation threshold of the sodium currents and increase the membrane resistance, augmenting the voltage change caused by any membrane current. Thus, in the cold, Na v 1.8 remains available as the sole electrical impulse generator in nociceptors that transmits nociceptive information to the central nervous system. Consistent with this concept is the observation that Na v 1.8-null mutant mice 3 show negligible responses to noxious cold and mechanical stimulation at low temperatures. Our data present strong evidence for a specialized role of Na v 1.8 in nociceptors as the critical molecule for the perception of cold pain and pain in the cold.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Action Potentials - drug effects / Animals / Biological and medical sciences / Cellular biology / Central nervous system / Cold / Cold Temperature / Cooling / Fibers / Fundamental and applied biological sciences. Psychology / Humanities and Social Sciences / Inactivation / letter / Low temperature / Membranes / Motor control and motor pathways. Reflexes. Control centers of vegetative functions. Vestibular system and equilibration / multidisciplinary / NAV1.8 Voltage-Gated Sodium Channel / Neurology / Neurons / Neurons, Afferent - drug effects / Neurons, Afferent - metabolism / Pain / Pain - metabolism / Pain - physiopathology / Perception / Proteins / Rats / Rats, Wistar / Science / Science (multidisciplinary) / Skin / Sodium / Sodium Channels - metabolism / Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors / Temperature / Tetrodotoxin - pharmacology / Vertebrates: nervous system and sense organs