Pain signalling pathways Nociceptors are different from other sensory neurons in that they have a low activating threshold and consequently increase their response to constant stimuli. Therefore, nociceptors are easily sensitised by agents such as
bradykinin and
nerve growth factor, which are released at the site of tissue injury, ultimately causing changes to ion channel conductance. VGSCs have been shown to increase in density after nerve injury. Therefore, VGSCs can be modulated by many different hyperalgesic agents that are released after nerve injury. Further examples include
prostaglandin E2 (PGE2),
serotonin and
adenosine, which all act to increase the current through Nav1.8. Prostaglandins such as PGE2 can sensitise nociceptors to thermal, chemical and mechanical stimuli and increase the excitability of DRG sensory neurons. This occurs because PGE2 modulates the trafficking of Nav1.8 by binding to G-protein-coupled
EP2 receptor, which in turn activates
protein kinase A. Protein kinase A phosphorylates Nav1.8 at intracellular sites, resulting in increased sodium ion currents. Evidence for a link between PGE2 and hyperalgesia comes from an antisense deoxynucleotide knockdown of Nav1.8 in the DRG of rats. Another modulator of Nav1.8 is the ε isoform of
PKC. This isoform is activated by the inflammatory mediator bradykinin and phosphorylates Nav1.8, causing an increase in sodium current in the sensory neurons, which promotes mechanical hyperalgesia.
Suzetrigine As of January 30th 2025,
suzetrigine (brand name Journavx) was approved by
FDA for management of acute moderate to severe pain, as a
first-in-class non-
opioid pain medication (thus avoiding the addictive potential associated with opioid medications). It works as a selective inhibitor of Nav1.8 channels on
peripheral nerves and as such has analgesic effect, preventing
nociceptive stimulus from reaching the brain by blocking signals in the peripheral nervous system.
Brugada syndrome Mutations in
SCN10A are associated with
Brugada syndrome.
Membrane trafficking Nerve growth factor levels in inflamed or injured tissues are increased creating an increased sensitivity to pain (hyperalgesia). The increased levels of nerve growth factor and
tumour necrosis factor-α (TNF-α) causes the upregulation of Nav1.8 in sensory neurons via the accessory protein
p11 (annexin II light chain). It has been shown using the
yeast-two hybrid screening method that p11 binds to a 28-amino-acid fragment at the N terminus of Nav1.8 and promotes its
translocation to the
plasma membrane. This contributes to the hyperexcitability of sensory neurons during pain. p11-null nociceptive sensory neurons in mice, created using the
Cre-loxP recombinase system, show a decrease in Nav1.8 expression at the plasma membrane. Therefore, disrupting the interactions between p11 and Nav1.8 may be a good therapeutic target for lowering pain. In
myelinated fibres, VGSCs are located at the
nodes of Ranvier; however, in unmyelinated fibres, the exact location of VGSCs has not been determined. Nav1.8 in unmyelinated fibres has been found in clusters associated with
lipid rafts along DRG fibers both
in vitro and
in vivo. Lipid rafts organise the cell membrane, which includes trafficking and localising ion channels. Removal of lipid rafts in the membrane using
MβCD, which depletes
cholesterol from the plasma membrane, leads to a shift of Nav1.8 to a non-raft portion of the membrane, causing reduced action potential firing and propagation. Genetic screening of patients with these idiopathic neuropathies has uncovered mutations in the
SCN9A gene, encoding the related channel Nav1.7. A
gain-of-function mutation in Nav1.7 located in the DRG sensory neurons was found in nearly 30% of patients with idiopathic small fiber neuropathy in one study. This gain-of-function mutation causes an increase in excitability (hyperexcitability) of DRG sensory neurons and thus an increase in pain. Nav1.7 thus been shown to be linked to human pain; Nav1.8, by contrast, had only been associated to pain in animal studies until recently. A gain-of-function mutation was found in the Nav1.8-encoding
SCN10A gene in patients with painful peripheral neuropathy. A study of 104 patients with
idiopathic peripheral neuropathies who did not have the mutation in
SCN9A used
voltage clamp and
current clamp methods, along with predictive
algorithms, and yielded two gain-of-function mutations in
SCN10A in three patients. Both mutations cause increased excitability in DRG sensory neurons and hence contribute to pain, but the mechanism by which they do so is not understood. == References ==