PMID- 19012501
OWN - NLM
STAT- MEDLINE
DCOM- 20090107
LR  - 20190917
IS  - 1744-7658 (Electronic)
IS  - 1354-3784 (Linking)
VI  - 17
IP  - 12
DP  - 2008 Dec
TI  - Voltage-gated sodium channels: the search for subtype-selective analgesics.
PG  - 1849-64
LID - 10.1517/13543780802514559 [doi]
AB  - 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/METHODS: 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. RESULTS/CONCLUSION: 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.
FAU - England, Steve
AU  - England S
AD  - Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, 
      Kent CT13 9NJ, UK. steve.england@pfizer.com
LA  - eng
PT  - Journal Article
PT  - Review
PL  - England
TA  - Expert Opin Investig Drugs
JT  - Expert opinion on investigational drugs
JID - 9434197
RN  - 0 (Analgesics)
RN  - 0 (Sodium Channels)
SB  - IM
MH  - Analgesics/classification/*pharmacology/therapeutic use
MH  - Animals
MH  - Humans
MH  - Ion Channel Gating/drug effects
MH  - Mutation/drug effects
MH  - Pain/drug therapy
MH  - Sodium Channels/genetics/*metabolism
RF  - 146
EDAT- 2008/11/18 09:00
MHDA- 2009/01/08 09:00
CRDT- 2008/11/18 09:00
PHST- 2008/11/18 09:00 [pubmed]
PHST- 2009/01/08 09:00 [medline]
PHST- 2008/11/18 09:00 [entrez]
AID - 10.1517/13543780802514559 [doi]
PST - ppublish
SO  - Expert Opin Investig Drugs. 2008 Dec;17(12):1849-64. doi: 
      10.1517/13543780802514559.