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.
Show evidence (3 references)
"This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons."
Establishes the trigger gene and the nociceptor-restricted expression that makes this module sensory-selective.
"SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors"
Establishes the second trigger gene of the module and the same nociceptor-restricted expression pattern.
"variants of genes coding for the voltage-gated sodium channels Nav1.8 (SCN10A) and Nav1.9 (SCN11A) lead to small-fibre neuropathy and congenital insensitivity to pain, respectively."
Supplies the citation for the third trigger gene, SCN10A, which the node names but which the other two evidence items do not cover, and states both clinical directions this module models. Evidence source is OTHER because this is a review.
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.
Show evidence (1 reference)
"In cells expressing mutant Na(v)1.7, the currents were no greater than background."
Direct electrophysiological demonstration of the loss-of-function branch: the mutant channel carries no measurable current.
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.
Show evidence (2 references)
"Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current."
Establishes the persistent-current mechanism of this branch.
"Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE)."
Establishes the hyperpolarized-activation mechanism as the distinct second route into this branch, in the same allelic series.
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.
Show evidence (1 reference)
"Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission."
Directly documents the crossing branch: excess channel activity at rest impairs rather than enhances action-potential generation.
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.
Show evidence (2 references)
"Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans."
Establishes this node as non-redundant and rate-limiting: nociception in humans depends on it and nothing substitutes for it.
"PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy."
Supports treating these disorders as one mechanistic class defined at this node while keeping their biophysical routes into it distinct.
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.
Show evidence (3 references)
"Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable."
Direct current-clamp demonstration that a gain-of-function Nav1.7 variant makes nociceptive neurons hyperexcitable, which is the claim this node makes.
"IEM is characterized clinically by burning pain and redness that is usually focused on the distal extremities, precipitated by mild warmth and relieved by cooling"
Supplies the clinical read-out of this node for the erythromelalgia conformer, including the innocuous-warmth trigger that makes the firing threshold shift observable at the bedside.
"Gain-of-function variants in the Na(v)1.7 sodium channel have recently been found in nearly 30% of patients with idiopathic SFN"
Establishes that this branch accounts for a substantial share of an apparently idiopathic painful neuropathy, extending the module beyond the rare Mendelian syndromes. Evidence source is OTHER because this is a review.
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.
Show evidence (2 references)
"The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype."
States the terminal phenotype of this branch and its selectivity: pain alone is lost, in an otherwise healthy individual.
"we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations."
Documents the same terminal phenotype reached through the depolarization block branch, and its injury consequences.