Can herpes zoster-triggered neuroimmune activation and inflammatory mediators sustain postherpetic neuropathic pain?

Herpes zoster can damage sensory ganglia and peripheral nerves; in some people, pain persists after rash healing as postherpetic neuralgia (PHN). The proposed inflammatory–neuroimmune mechanism is biologically credible, but its persistence and causal importance in established human PHN vary.

Clinical and mechanistic evidence

• Sensory-neuron hyperexcitability is a supported contributor to pain after rash resolution. Lowered nociceptor thresholds and ectopic firing can sustain neuropathic pain, while dorsal-horn amplification and central sensitization further maintain pain independently of visible cutaneous inflammation.
• Cytokines and chemokines including TNF-α, IL-1β, and IL-6 can sensitize primary sensory neurons by increasing activity of TRPV1, P2X3, and voltage-gated sodium channels. These changes offer a coherent pathway from immune signaling to spontaneous firing, allodynia, and persistent pain.
• Glial signaling in sensory ganglia and spinal cord can amplify dorsal-horn excitability and NMDA-dependent transmission. This provides an additional route by which neuroimmune activity may promote central sensitization after the eruption resolves.

Persistence of inflammation

• Evidence that inflammatory activity remains elevated in established PHN is mixed. Some post-healing studies found little systemic or cutaneous cytokine difference and no association between local cytokines and pain.
• Conversely, a prospective cohort reported persistently elevated serum IL-6, TNF-α, and C-reactive protein in people who developed PHN. These findings support persistent inflammatory signaling in at least a subset of patients, but do not establish a universal or locally causal mechanism.

Bottom line

• Persistent neuroimmune activation and inflammatory mediators are plausible contributors to post-zoster nociceptor sensitization and pain, particularly through cytokine-driven peripheral excitability and glial-mediated central sensitization. However, established PHN is likely heterogeneous: structural sensory-axon loss, deafferentation, and maladaptive central plasticity may coexist with—or sometimes predominate over—ongoing inflammation.