This is a mechanism module, not a specific disease. It is the peripheral sensory counterpart of `cardiac_ion_channel_repolarization`, and is deliberately scoped to the channel-intrinsic arm of hereditary pain disorders. It is NOT a duplicate of `peripheral_axonal_degeneration`: in the canonical conformers the nociceptor is electrically abnormal but structurally intact, and no axon degenerates. The exception is the small-fibre-neuropathy branch, where sustained Nav1.7 hyperexcitability is associated with distal small-fibre degeneration; an entry curating that branch should conform to both modules. The developmental route to pain insensitivity — NTRK1/NGF trophic failure and PRDM12 nociceptor specification, which cause loss of the nociceptors themselves rather than of their excitability — is mechanistically distinct and deliberately OUT of scope; a disease such as congenital insensitivity to pain with anhidrosis conforms only through its channelopathy nodes, if it has any.
Disorder-specific substitutions at the trigger node: biallelic SCN9A nonsense variants (autosomal recessive congenital insensitivity to pain); SCN9A missense variants shifting activation to more negative potentials (inherited erythromelalgia); SCN9A missense variants impairing fast inactivation and producing persistent current (paroxysmal extreme pain disorder); SCN9A gain-of-function variants of intermediate severity (idiopathic small-fibre neuropathy); SCN11A/Nav1.9 gain-of-function (either familial episodic pain or, when the resting depolarization is large enough to inactivate the action-potential machinery, congenital pain insensitivity); SCN10A/Nav1.8 gain-of-function (painful small-fibre neuropathy).
The two directional branches are NOT interchangeable conformance targets. A conforming entry attaches to the branch its evidence actually supports, and to the shared `#Nociceptor Action Potential Threshold and Firing` node only when the entry evidences an effect on nociceptor firing itself rather than merely carrying a variant in one of these genes. Curating a channel variant with no demonstrated effect on nociceptor excitability does not conform.
Not an Xogenesis module: nothing pathological is formed; the terminal output is altered function of an intact cell.
Does pharmacological blockade of Nav1.7 in adults reproduce the profound, selective analgesia of congenital Nav1.7 loss of function?
KNOWLEDGE GAP
nav17_analgesic_translation_gap
Attached to:
Nociceptor Action Potential Threshold and Firing
The human genetics at this node are as clean as pain biology gets — biallelic SCN9A loss of function abolishes pain with no other neurological deficit — and that result has driven two decades of selective Nav1.7 blocker development. Repeated clinical programmes have nonetheless failed to reproduce the genetic phenotype pharmacologically. Whether the gap reflects incomplete channel occupancy, a developmental component of the congenital phenotype that acute blockade cannot recapitulate, or a contribution from opioid-peptide upregulation that accompanies lifelong Nav1.7 loss is unresolved. Curators should not treat the genetic evidence at this node as evidence that Nav1.7 blockade is an effective analgesic strategy.
Proposed experiments:
Target-occupancy-anchored trial of selective Nav1.7 blockade
Nociceptor Voltage-Gated Sodium Channel Variant
trigger
A germline variant in one of the three voltage-gated sodium channel alpha-subunits whose expression is concentrated in nociceptive dorsal-root-ganglion and trigeminal neurons: SCN9A (Nav1.7), SCN10A (Nav1.8) or SCN11A (Nav1.9). Their restricted expression is what makes these channels a non-redundant, dose-sensitive control point for pain rather than a general determinant of excitability, and it is why the resulting syndromes are sensory-selective and — for Nav1.7 loss — otherwise silent.
Downstream
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Loss of Nociceptor Sodium Current
Nonsense or otherwise inactivating variants remove the channel's contribution to the nociceptor sodium current.
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Enhanced or Persistent Nociceptor Sodium Current
Missense variants that shift activation negative or impair fast inactivation increase current at or near resting potential.
Loss of Nociceptor Sodium Current
amplifier
The loss-of-function branch. Truncating or otherwise inactivating variants abolish the channel's current, removing the subthreshold amplification that normally lets a receptor potential reach action-potential threshold. Because the channel is non-redundant in nociceptors, no other sodium channel compensates, and the deficit is specific to pain signalling.
Downstream
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Nociceptor Action Potential Threshold and Firing
Without the amplifying sodium current the nociceptor cannot reach firing threshold.
Enhanced or Persistent Nociceptor Sodium Current
amplifier
The gain-of-function branch, which splits by biophysical mechanism — a distinction that predicts both the clinical syndrome and the drug response, and that conformers must preserve rather than collapsing into a generic "gain of function". Variants shifting voltage-dependence of activation to more negative potentials open the channel to ordinary warmth-level depolarizations (the inherited erythromelalgia mechanism). Variants impairing fast inactivation leave a persistent, non-inactivating sodium current (the paroxysmal extreme pain disorder mechanism). A third pattern, excessive channel activity at resting voltage, produces sustained depolarization rather than enhanced firing and is routed separately below.
Downstream
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Nociceptor Action Potential Threshold and Firing
Increased sodium current at and near rest lowers the threshold for action-potential generation.
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Sustained Nociceptor Depolarization and Conduction Block
When the excess current is active at resting voltage rather than during the upstroke, the nociceptor depolarizes instead of firing more.
Sustained Nociceptor Depolarization and Conduction Block
amplifier
The module's counterintuitive crossing branch, and the reason it is curated bidirectionally rather than as two separate one-way modules. A gain-of-function variant whose excess activity falls at resting membrane potential holds the nociceptor tonically depolarized. That sustained depolarization inactivates the action-potential machinery, so the cell can no longer fire or transmit — a biophysical gain producing a clinical loss. It is the mechanism by which SCN11A gain-of-function causes congenital pain insensitivity, and it means the sign of the channel defect cannot be inferred from the patient's phenotype or vice versa.
Downstream
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Nociceptor Action Potential Threshold and Firing
Depolarization block removes the nociceptor's ability to generate and propagate action potentials.
Nociceptor Action Potential Threshold and Firing
central effector
The rate-limiting, disorder-agnostic node of this module and its key conformance target. Every arm — loss of current, enhanced or persistent current, and depolarization block — converges here, on whether and how readily the nociceptor generates and propagates action potentials in response to a stimulus. Shifted downward, the neuron fires spontaneously and to innocuous stimuli; abolished, noxious stimuli produce no signal at all. The clinical phenotype is read off the direction and magnitude of the shift at this node, not off the direction of the underlying channel defect.
Downstream
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Nociceptor Hyperexcitability and Ectopic Firing
A lowered threshold produces spontaneous and stimulus-evoked overfiring.
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Failure of Nociceptive Signal Transduction
An abolished or blocked action potential leaves noxious stimuli unsignalled.
Nociceptor Hyperexcitability and Ectopic Firing
effector
Nociceptors fire spontaneously and in response to stimuli that would not normally be painful, so that ordinary warmth, exercise, or defecation triggers a barrage of nociceptive input. Conforming entries substitute the disorder-specific trigger and territory: heat-provoked, cooling-relieved distal extremity flares in inherited erythromelalgia; paroxysms in rectal, ocular and submandibular territory in paroxysmal extreme pain disorder; distal burning pain with autonomic complaints in small-fibre neuropathy.
Failure of Nociceptive Signal Transduction
effector
No nociceptive signal reaches the spinal cord, whether because the amplifying current is absent or because the neuron is held in depolarization block. The nociceptors themselves are present and structurally normal — which is what distinguishes this node from the developmental NGF-TRKA/PRDM12 route to pain insensitivity, where the neurons are lost. Other sensory modalities and autonomic function are spared, so the deficit is a selective, complete and painless anaesthesia to noxious stimuli, with injury, mutilation and unrecognized fracture as its consequences.