Sodium channels Nav1.7, Nav1.8 and pain; two distinct mechanisms for Nav1.7 null analgesia

Federico Iseppon; Alexandros H Kanellopoulos; Naxi Tian; Jun Zhou; Gozde Caan; Riccardo Chiozzi; Konstantinos Thalassinos; Cankut Çubuk; Myles J Lewis; James J Cox; Jing Zhao; Christopher G Woods; John N Wood

doi:10.1016/j.ynpai.2024.100168

Sodium channels Na_v1.7, Na_v1.8 and pain; two distinct mechanisms for Na_v1.7 null analgesia

Neurobiol Pain. 2024 Oct 11:16:100168. doi: 10.1016/j.ynpai.2024.100168. eCollection 2024 Jul-Dec.

Authors

Affiliations

¹ Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK.
² Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.
³ University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK.
⁴ 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.
⁵ Cambridge Institute for Medical Research, Keith Peters Building, Biomedical Campus, Hills Rd, Cambridge CB2 0XY, UK.

Abstract

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_v1.7 and Na_v1.8. Genetic deletion of Na_v1.8 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_v1.7 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_v1.7 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_v1.7 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_v1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Na_v1.7 channel. Here we show that sensory neuron sodium channels Na_v1.1, Na_v1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Na_v1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Na_v1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.

Keywords: Drugs; Genetic deletion; Nav1.7; Nav1.8; Pain; Side effects; Sodium channels.