Tissue Injury Triggers an Inflammatory Cascade
Damaged cells and immune cells flood the wound with signaling molecules.
- 12+: Mediators released (cytokines, prostaglandins, NGF)
- Minutes: Mast cell response (after injury onset)
- 4: NGF source cells (fibroblasts, keratinocytes, immune cells)
- ↓ acidic: Local pH shift (sensitizes nerve endings)
Injury triggers a chemical alarm
Torn or infected tissue releases danger signals fast.
Mast cells and macrophages arrive
Immune cells amplify the response with more mediators.
NGF joins the inflammatory soup
Fibroblasts and keratinocytes start producing extra NGF.
NGF Concentration Rises Around Nerve Endings
Local NGF levels climb well above baseline near injured tissue.
- 10–50×: NGF increase (above healthy tissue baseline)
- ~mm: Diffusion radius (around injury site)
- Arthritis, cystitis: Detected in (chronic pain conditions)
- Hours: Half-life (sustained by ongoing inflammation)
NGF diffuses toward nociceptors
Molecules drift from inflamed tissue to nerve terminals.
Concentration tracks inflammation severity
Worse inflammation means more NGF reaching nerves.
Chronic conditions sustain the surge
Persistent inflammation keeps NGF elevated for weeks.
NGF Binds and Activates TrkA Receptors
TrkA on nociceptor terminals recognizes NGF and switches on.
- TrkA: Receptor (tyrosine kinase receptor)
- p75NTR: Co-receptor (modulates binding affinity)
- Dimerization: Activation trigger (auto-phosphorylation cascade)
- Seconds: Response time (to minutes for full activation)
NGF docks onto TrkA
Binding causes two receptors to pair up.
Kinase domains cross-phosphorylate
Paired receptors activate their internal signaling tails.
Downstream cascades switch on
MAPK and PI3K pathways begin propagating the signal.
Signaling Travels to the Nucleus and Rewrites Gene Expression
Activated TrkA signals retrogradely, boosting pain-channel gene transcription.
- Retrograde axonal: Transport route (endosome to soma)
- NaV1.8: Key channel (sodium channel upregulated)
- TRPV1: Key receptor (heat/capsaicin receptor upregulated)
- Hours–days: Onset (for new protein synthesis)
Signaling endosomes travel to soma
Active TrkA complexes ride the axon to the nucleus.
Transcription factors switch genes on
CREB and others boost channel gene expression.
New proteins reach the membrane
Newly made channels traffic back to nerve terminals.
Peripheral Sensitization Lowers the Pain Threshold
Extra channels make the nociceptor fire at weaker stimuli.
- ↓ 30–70%: Threshold shift (less stimulus needed to fire)
- Allodynia: Clinical term (pain from normally mild stimuli)
- Hyperalgesia: Related term (exaggerated pain response)
- Anti-NGF mAbs: Therapeutic target (tanezumab and similar drugs)
Channel density keeps rising
More NaV1.8 and TRPV1 sit on the membrane.
Firing threshold keeps falling
Light touch or warmth now triggers pain signals.
Chronic pain state consolidates
Sensitization can persist after the original injury heals.