The roles of sodium channels in nociception: Implications for mechanisms of pain.
Understanding the role of voltage-gated sodium channels in nociception may provide important insights into pain mechanisms. Voltage-gated sodium channels are critically important for electrogenesis and nerve impulse conduction, and a target for important clinically relevant analgesics such as lidocaine. Furthermore, within the last decade studies have shown that certain sodium channel isoforms are predominantly expressed in peripheral sensory neurons associated with pain sensation, and that the expression and functional properties of voltage-gated sodium channels in peripheral sensory neurons can be dynamically regulated following axonal injury or peripheral inflammation. These data suggest that specific voltage-gated sodium channels may play crucial roles in nociception. Experiments with transgenic mice lines have clearly implicated Na(v)1.7, Na(v)1.8 and Na(v)1.9 in inflammatory, and possibly neuropathic, pain. However the most convincing and perhaps most exciting results regarding the role of voltage-gated sodium channels have come out recently from studies on human inherited disorders of nociception. Point mutations in Na(v)1.7 have been identified in patients with two distinct autosomal dominant severe chronic pain syndromes. Electrophysiological experiments indicate that these pain-associated mutations cause small yet significant changes in the gating properties of voltage-gated sodium channels that are likely to contribute substantially to the development of chronic pain. Equally exciting, recent studies indicate that recessive mutations in Na(v)1.7 that eliminate functional current can result in an apparent complete, and possibly specific, indifference to pain in humans, suggesting that isoform specific blockers could be very effective in treating pain. In this review we will examine what is known about the roles of voltage-gated sodium channels in nociception.
Cummins
Theodore R
TR
Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, 950 West Walnut Street, R2 468, Indianapolis, IN 46202, United States Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, United States Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, United States Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, CT 06516, United States.
Sheets
Patrick L
PL
Waxman
Stephen G
SG
D000818:Animals; D006801:Humans; D015640:Ion Channel Gating; D008959:Models, Neurological; D009475:Neurons, Afferent; D009619:Nociceptors; D010146:Pain / Q000503:physiopathology*; D017288:Pain Threshold; D015222:Sodium Channels
D015222:Sodium Channels