Understanding the genetic basis of congenital insensitivity to pain.
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Publication Date
2020-05-15Journal Title
Br Med Bull
ISSN
0007-1420
Publisher
Oxford University Press (OUP)
Volume
133
Issue
1
Pages
65-78
Language
eng
Type
Article
This Version
AM
Physical Medium
Print
Metadata
Show full item recordCitation
Drissi, I., Woods, W. A., & Woods, G. (2020). Understanding the genetic basis of congenital insensitivity to pain.. Br Med Bull, 133 (1), 65-78. https://doi.org/10.1093/bmb/ldaa003
Abstract
INTRODUCTION OR BACKGROUND: Congenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders. CIP individuals demonstrate the unexpectedly severe consequences of painlessness. Although only a small number of causative conditions and genes are known, most have led to profound insights into human nociception. CIP gene discovery is catalyzing the manufacture of completely new classes of analgesics, and these are needed as alternatives to synthetic highly potent opioids. SOURCES OF DATA: Pubmed.gov peer-reviewed journal articles and reviews. AREAS OF AGREEMENT: The importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing.New analgesics can be generated from knowledge of the NGF-TRKA nociceptor pathway.Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling.Mutations in the voltage-gated sodium channels SCN9A and SCN11A can cause congenital painlessness, and in contradistinction, other mutations can cause episodic neuropathic pain. SCN9A/Nav1.7 is an analgesic target. SCN11A/Nav1.9 is unlikely to be an analgesic target.There are further Mendelian causes of painlessness to be discovered. AREAS OF CONTROVERSY: Which NGF-TRKA intracellular signalling pathways operate in nociceptor development and which in post-natal pain sensing?Why have no clinically effective Nav1.7 antagonist been generated? SCN9A-CIP causes analgesia, at least in part, through endogenous opioids.Why do all CIP phenotypes involve a complete loss of all types of nociception? AREAS TIMELY FOR DEVELOPING RESEARCH: PRDM12 as an analgesic target.Discovery of the function and analgesic potential of new CIP genes.Can NGF-TRKA be used in the treatment of S. aureus?
Keywords
Humans, Pain Insensitivity, Congenital, Nerve Tissue Proteins, Signal Transduction, Drug Discovery, Nociception, Pharmacogenomic Testing
Sponsorship
Wellcome Trust
Cambridge NIHR Biomedical Research Centre
Funder references
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1415-50)
Biotechnology and Biological Sciences Research Council (BB/N504142/1)
Wellcome Trust (via University College London (UCL)) (532344)
Identifiers
External DOI: https://doi.org/10.1093/bmb/ldaa003
This record's URL: https://www.repository.cam.ac.uk/handle/1810/302789
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