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.

Aquaporin-1 Tunes Pain Perception by Interaction with Nav1.8 Na+ Channels in Dorsal Root Ganglion Neurons

“…High dose capsaicin, thus, sensitizes a different subtype of DRG neurons. We found here that low dose capsaicin, which evokes a near-pure thermal hyperalgesia without C-fiber destruction (27,33), produced much reduced pain perception in the AQP1 Ϫ/Ϫ mice. Remarkable phenotype differences were also found upon challenge with bradykinin and PGE 2 , which are major components of the inflammatory soup and sensitize small DRG neurons through G protein-coupled receptors targeting TTX-R and TRP channels (43).…”

“…The immunoprecipitation and single molecule tracking indicated a physical interaction between AQP1 and Na v 1.8. Impairment in cold pain sensing in the AQP1 Ϫ/Ϫ mice provides further evidence for involvement of AQP1 in the Na v 1.8 cold pain signaling pathway (27,33).…”

“…(e) For formalin testing, total licking time in 5-min intervals over 40 min was measured after intraplantar injection of 10 l of 5% formalin in saline. (f) For cold pain testing, a cold-plate (model #35100, Ugo Basile) maintained at 4°C was used to assess noxious cold sensitivity of the plantar surface of the hind paws (27). Mice were placed on the cold plate for 5 min, and behavior was videoed and scored in a blinded manner.…”

Molecular sensors and modulators of thermoreception

“…96 However, in other studies, A type K C currents and voltage gated Na C currents were thought to be critical in specifying cold activation threshold of TRPM8 C neurons. 94,97,98 It is possible that a complex interplay and concerted action of different ion conductance shape the excitability of TRPM8 C neurons. What remains little known is why TRPM8 per se exhibits different cold sensitivities in different subpopulation of neurons and what determine the varied cold sensitivity of TRPM8.…”

Exon 11 skipping ofSCN10Acoding for voltage-gated sodium channels in dorsal root ganglia

“…Together with the N-and C-termini, these loops are involved in the regulation of channel functions by means of posttranslational modification and interaction with various intracellular signaling molecules. 2 Na V 1.8 is primarily expressed in afferent neurons of dorsal root ganglia (DRG); 3,4 it is involved in pain signaling 5,6 and its activity is highly regulated. For example, Na V β 3 interacts with the rat Na V 1.8 channel and masks a putative ER retention motif (sequence RRR) in the domain I/II linker, thus leading to enhanced surface expression of Na V 1.8.…”