Subunit and frequency-dependent inhibition of Acid Sensing Ion Channels by local anesthetic tetracaine

Extracellular acidosis is a prominent feature of multiple pathological conditions, correlating with pain sensation. Acid-sensing ion channels (ASICs), a family of proton-gated cation channels, are distributed throughout the central and peripheral nervous systems. Activation of ASICs, particularly ASIC3 and ASIC1a channels, by acidic pH and the resultant depolarization of nociceptive primary sensory neurons, participates in nociception. Agents that inhibit the activation of ASICs are thus expected to be analgesic. Here, we studied the effect of local anesthetic tetracaine on ASIC currents.

Tetracaine inhibited the peak ASIC3 current in a concentration-dependent manner with an IC₅₀ of 9.96 ± 1.88 mM. The degree of inhibition by tetracaine was dependent on the extracellular pH but independent of the membrane potential. Furthermore, 3 mM tetracaine also inhibited 29.83% of the sustained ASIC3 current. In addition to ASIC3, tetracaine inhibited the ASIC1a and ASIC1β currents. The inhibition of the ASIC1a current was influenced by the frequency of channel activation. In contrast to ASIC3, ASIC1a, and ASIC1β currents, ASIC2a current was not inhibited by tetracaine. In cultured mouse dorsal root ganglion neurons, 1–3 mM tetracaine inhibited both the transient and sustained ASIC currents. At pH4.5, 3 mM tetracaine reduced the peak ASIC current to 60.06 ± 4.51%, and the sustained current to 48.24 ± 7.02% of the control values in dorsal root ganglion neurons. In contrast to ASICs, voltage-gated sodium channels were inhibited by acid, with 55.15% inhibition at pH6.0 and complete inhibition at pH5.0.

These findings disclose a potential new mechanism underlying the analgesic effects of local anesthetics, particularly in acidic conditions where their primary target (i.e. voltage-gated Na⁺ channel) has been suppressed by protons.