Nonaddictive Analgesia: New Approaches That Target the Hodgkin-Huxley NaV/KV Dyad

Résumé fourni par la source

Chronic pain represents a massive global health burden that is exacerbated by the limitations and liabilities of opioid therapies. This review examines the biophysical basis of nociceptor excitability, framed by the Hodgkin-Huxley dyad of opposing voltage-gated sodium (Na V ) and potassium (K V ) conductances. We analyze the roles of peripheral Na V isoforms (Na V 1.7, Na V 1.8, Na V 1.9) as drivers of pathological firing and discuss the translational trajectory of Na V inhibitors, ranging from the recent clinical approval of Na V 1.8-selective small molecules to the ongoing challenges facing Na V 1.7-targeted programs. Beyond canonical pore blockers, we evaluate emerging modalities, including state-dependent cannabinoid modulation, targeted protein degradation, and genetic interventions. Complementing these excitatory targets, we discuss K V 7 channel activators as molecular brakes capable of buffering hyperexcitability. Finally, we propose that rational comodulation of this dyad offers a mechanistically grounded pathway toward effective, nonaddictive analgesia.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.