Sodium channels Na v 1.7, Na v 1.8 and pain; two distinct mechanisms for Na v 1.7 null analgesia.

Autor: Iseppon F; Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK., Kanellopoulos AH; Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK., Tian N; Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK., Zhou J; Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK., Caan G; Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK., Chiozzi R; Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.; University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK., Thalassinos K; Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.; University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK., Çubuk C; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK., Lewis MJ; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK., Cox JJ; Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK., Zhao J; Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK., Woods CG; Cambridge Institute for Medical Research, Keith Peters Building, Biomedical Campus, Hills Rd, Cambridge CB2 0XY, UK., Wood JN; Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK.
Jazyk: angličtina
Zdroj: Neurobiology of pain (Cambridge, Mass.) [Neurobiol Pain] 2024 Oct 11; Vol. 16, pp. 100168. Date of Electronic Publication: 2024 Oct 11 (Print Publication: 2024).
DOI: 10.1016/j.ynpai.2024.100168
Abstrakt: Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Na v 1.7 and Na v 1.8. Genetic deletion of Na v 1.8 in mice leads to a loss of pain and antagonists are effective analgesics. The situation with Nav1.7 is more complex. Complete embryonic loss of Na v 1.7 in humans or in mouse sensory neurons leads to anosmia as well as profound analgesia as a result of diminished neurotransmitter release. This is mediated by enhanced endogenous opioid signaling in humans and mice. In contrast, anosmia is opioid-independent. Sensory neuron excitability and autonomic function appear to be normal. Adult deletion of Na v 1.7 in sensory neurons also leads to analgesia, but through diminished sensory and autonomic neuron excitability. There is no opioid component of analgesia or anosmia as shown by a lack of effect of naloxone. Pharmacological inhibition of Na v 1.7 in mice and humans leads both to analgesia and dramatic side-effects on the autonomic nervous system with no therapeutic window. These data demonstrate that specific Na v 1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Na v 1.7 channel. Here we show that sensory neuron sodium channels Na v 1.1, Na v 1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Na v 1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Na v 1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2024 The Author(s).)
Databáze: MEDLINE
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