Table 3.

Specific Pain Targets

SELECTED SPECIFIC PAIN MECHANISMS	PRECLINICAL MANIFESTATION	SPECIFIC CLINICAL MANIFESTATION	MOLECULAR TARGET	GENETIC VALIDATION	SPECIFIC TREATMENT
Increased NGF synthesis	Nociceptor activation at lowered heat threshold	Peripheral sensitization No specific diagnostic criteria	TrkA (NGF receptor); TRPV1	HSAN IV HSAN V	anti-NGF AB (phase 3); TrkA R antagonist (phase 2)
NMDA receptor phosphorylation	Increased post-synaptic activity	Pain amplification No specific diagnostic criteria	NMDA receptor	no	NMDA receptor antagonist (e.g. Ketamine)
Excitatory transmitter release	Increased post-synaptic activity	Pain amplification No specific diagnostic criteria	Ca(v)α2δ-1	no	Gabapentinoids
Nav 1.7 hyperexcitability	Increased nociceptor firing	Paroxysmal extreme pain disorder; primary erythromelalgia	Nav 1.7	paroxysmal extreme pain disorder; primary erythromelalgia	Nav 1.7 antagonist (phase 2)
Spinal interneuron degeneration	Decreased inhibitory transmission	Pain amplification No specific diagnostic criteria	Gaba A receptor	no	Gaba A receptor subtype selective agonist
TRPA1 sensitization	Increased nociceptor firing	familial episodic pain syndrome	TRPA1	familial episodic pain syndrome	TRPA1 antagonist

NOTE. Molecular targets identified by preclinical models and sometimes rare human genetic mutations. Clinical identification of these molecular mechanisms remains the most challenging and least developed step on the pain ladder, owing to the absence of any diagnostic tools/biomarkers. Some specific treatment options are available or in clinical development, but identification for these mechanisms in patient to select specific treatments remains the biggest challenge.