Acid-sensing ion channels in pain and psychiatric disorders: from basic properties to comorbidity mechanisms

Acid-sensing ion channels (ASICs) are proton-gated cation channels that mediate Na + and Ca 2+ influx upon activation by extracellular acidification. Beyond protons, endogenous ligands, toxins, and small molecules modulate ASIC gating through direct or synergistic mechanisms. ASICs have emerged as key players in pain and psychiatric disorders. Tissue acidosis drives hyperalgesia via sustained ASIC activation, synaptic plasticity disruption, and central sensitization, thereby promoting chronic pain. In limbic circuits, ASIC1a expression in the amygdala, periaqueductal gray, and dorsal raphe nucleus links these channels to anxiety and depression, with ASIC1a antagonists demonstrating robust efficacy in preclinical models. Selective ASIC modulators represent promising therapeutic candidates for pain-psychiatric comorbidities. This review integrates ASIC biophysical properties with their molecular and circuit-level mechanisms in disease, offering a framework to guide future translational efforts targeting ASIC-mediated pathologies.