Voltage-gated sodium channels: the search for subtype-selective analgesics.
BACKGROUND
Primary afferent or sensory neurons innervate almost all the tissues of the body. They are vital in receiving sensory information and conveying this to the spinal cord and subsequently to the brain, where the higher centres convert this afferent input into an 'understanding' of its nature. The nociceptors are a subset of sensory neurons responsible for the transmission of 'painful' stimuli into the CNS.


OBJECTIVE
Voltage-gated sodium channels (VGSCs) are pivotal in the transduction of noxious signals at the terminals of the nociceptors and the transmission of the signal along the axon and into the spinal cord and brain. There are nine functional members of the VGSC family. This review aims to briefly summarise the biology of the family, discuss those VGSCs involved in the transduction and transmission of nociceptive signals and to highlight the potential and also the challenges in seeking subtype-selective VGSC modulators for the effective treatment of pain.


CONCLUSIONS
Robust evidence from preclinical models - and better yet, overwhelming human clinical genetic data - provides a compelling rationale for the involvement of VGSCs in nociceptive processing. Some compounds showing a low degree of subtype selectivity have been progressed into clinical development, but the results have been disappointing. It is likely that the high degree of structural homology within the VGSC family is a causative factor in making the discovery of subtype-selective modulators extremely challenging. A much greater understanding of the structure - function relationship for VGSCs and pharmacological modulators is needed if we are to design the compounds that will target those channels involved in nociceptive signalling whilst sparing those in the heart and brain. Only then will we be able to deliver a quantum leap in analgesic pharmacotherapy, providing the effective and well-tolerated drugs that the patient needs.
England
Steve
S
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Kent CT13 9NJ, UK. steve.england@pfizer.com
D000700:Analgesics / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D009154:Mutation / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
D000700:Analgesics; D015222:Sodium Channels