title: Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures.
abstract: Sensory acuity and motor dexterity deteriorate when human limbs cool down, but pain perception persists and cold-induced pain can become excruciating. 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 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.
authors.affiliation: Department of Physiology and Pathophysiology, Faculty of Medicine, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. zimmermann@physiologie1.uni-erlangen.de
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
authors.forename: Alexandru
authors.initials: A
authors.lastname: Babes
authors.forename: Cruz Miguel
authors.initials: CM
authors.lastname: Cendan
authors.forename: Richard W
authors.initials: RW
authors.lastname: Carr
authors.forename: Jin-ichi
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Carla
authors.initials: C
authors.lastname: Nau
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003080:Cold Temperature; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin