technologies provided further understanding with the characterization of ion channels , particularly the sodium , potassium and calcium channels . Further research led to the discovery of several subtypes of sodium channels and the realization that some types are specific to peripheral nervous system .
Perception of acute pain is dependent upon firing of neurons in the dorsal root ganglia ( DRGs ) or the trigeminal ganglion ( facial pain ); generation of action potentials in these neurons depends on activation of sodium channels . Voltage gated sodium channels ( Nav ) 1.1 , 1.2 and 1.6 are exclusive to the central nervous system , 1.5 is specific to cardiac muscle and 1.4 to skeletal muscles . Channels 1.7 , 1.8 and 1.9 are exclusively seen in the peripheral nervous system 2 . Nav1.7 encoded by gene SCN9A boosts subthreshold depolarization in neurons of DRGs , sympathetic ganglia and the trigeminal ganglion . Nav 1.8 encoded by gene SCN10A can provoke repetitive firing in the same neurons . Nav1.9 encoded by gene SCN11A modulates resting membrane potential and amplifies response to depolarization . Among these channels , Nav1.8 is particularly important in pain . Jones et al 3 studied a highly selective inhibitor of Nav 1.8 , named VX-548 and noted in a recent study that postoperative pain was well-controlled with no major side effects . The drug has already received FDA ’ s Breakthrough Therapy Designation . This study has the potential to stimulate discovery of many more drugs that selectively inhibit Nav 1.8 with the availability of new technology such as messenger RNA editing and targeted protein degradation . 2 Blocking of all three peripheral sodium channels may have the potential to control postoperative pain eliminating the need for the use of opioid drugs . Perhaps they may also have a role in control of chronic pain from conditions such as peripheral neuropathies .
The phenomenal advances in molecular biology and genetics have opened the floodgates for discovery of drugs that target the underlying molecular basis of disorders with unprecedented precision . Perhaps with the discovery of many selective voltage gated peripheral sodium channel blockers , the use of opioid drugs will become a thing of the past and thereby make a major dent in the ongoing epidemic of narcotic addiction .
All this discussion about the story of discovery of voltage gated sodium channels reminded me of a famous quote from the poet and engraver William Blake : “‘ What is now proved was once only imagined .”
References :
1
Clarke H et al . Rates and risk factors for prolonged opioid use after major surgery : population-based cohort study . BMJ 2024 ; 348 g1251
2
Waxman SG Targeting a peripheral sodium channel to treat pain . NEJM 2023 ; 389 : 466-469
3
Jones J et al . Selective inhibition of Na 1.8 with CX-548 for acute pain NEJM 2023 ; 389:393-405
Dr . Iyer practices at the Neurodiagnostic Center of Louisville and is a retired professor of neurology at the University of Louisville School of Medicine .
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