A Quiet Nerve — NaV1.8 Closed, No Signal
At rest, peripheral pain-sensing neurons stay silent.
- −60 mV: Resting potential (polarized axon membrane)
- Closed: NaV1.8 state (no sodium influx)
- 0: Pain signal (no firing)
- Peripheral: Channel location (DRG sensory neurons)
NaV1.8 — a pain-specific sodium channel
NaV1.8 sits mainly in peripheral nociceptors.
It stays closed until injury depolarizes the membrane.
That peripheral restriction is what makes it druggable.
Why this channel, not opioid receptors
Opioids act centrally on brain and spinal receptors.
NaV1.8 blockers act only at the peripheral nerve.
No central nervous system engagement, no addiction liability.
Injury Depolarizes The Membrane
Damage triggers local depolarization and channel opening.
- Injury: Trigger (mechanical, thermal, chemical)
- Depolarizing: Membrane shift (toward threshold)
- Begins: NaV1.8 opening (voltage-gated response)
- ~−40 mV: Threshold (activation onset)
From damage to depolarization
Injured tissue releases inflammatory mediators nearby.
These mediators lower the nociceptor firing threshold.
NaV1.8 channels begin swinging open in response.
Severity scales the response
Higher injury severity opens more channels faster.
More open channels mean a stronger action potential.
The slider directly drives this depolarization intensity.
Sodium Influx Drives The Pain Signal Onward
Na⁺ rushing through NaV1.8 propagates the action potential.
- Na⁺: Ion driving AP (through NaV1.8 pore)
- ~90%: AP propagation (unblocked baseline)
- Fast: Conduction (along peripheral axon)
- Spinal cord: Destination (then central relay)
Regenerative sodium influx
Each open channel lets Na⁺ flood into the axon.
That local depolarization opens the next channel downstream.
The wave self-propagates the length of the fiber.
Unblocked, pain reaches the spine
Without a blocker, the signal travels essentially unimpeded.
Stronger injury severity produces a taller, faster wave.
This is the pathway suzetrigine intervenes on.
Suzetrigine Plugs The NaV1.8 Pore
The drug binds selectively, physically blocking the channel.
- Suzetrigine: Drug (brand name Journavx)
- NaV1.8: Target (selective, not NaV1.1–1.7)
- Pore block: Mechanism (state-dependent binding)
- 0% engaged: Opioid receptors (no binding at all)
Selective, non-opioid blockade
Suzetrigine binds the NaV1.8 pore with high selectivity.
Higher concentration means more channels get plugged.
Selectivity spares other sodium channels and the heart.
Concentration-dependent effect
The drug-concentration slider sets blockade percentage directly.
More blocked channels shrink the propagating wave.
This is a dose-response relationship, visualized live.
Suzetrigine engages 0% opioid receptors — the analgesia bypasses the addiction pathway entirely.
Propagation Halts At The Peripheral Nerve
Blocked NaV1.8 channels stop the pain signal before the spine.
- Near 0%: AP propagation (wave collapses at blockade)
- Minimal: Pain signal (signal does not reach CNS)
- 0%: Opioid involvement (always, by mechanism)
- Peripheral: Site of action (nerve, not brain)
A wave that cannot finish
Enough blocked channels break the regenerative chain.
The action potential shrinks and stops mid-axon.
No signal reaches the spinal cord or brain.
Analgesia without the opioid pathway
Pain relief here needs no mu-opioid receptor activity.
That separation removes tolerance and addiction risk.
Peripheral, mechanism-specific pain control at the source.
This is the core promise of Journavx: opioid-level relief for some pain, zero opioid receptor engagement.