Indomethacin inhibits tetrodotoxin-resistant Na+ channels at acidic pH in rat nociceptive neurons

摘要

Non-steroidal anti-inflammatory drugs (NSAIDs) are well-known inhibitors of cyclooxygenases (COXs) and are widely used for the treatment of inflammatory pain; however several NSAIDs display COX independent analgesic action including the inhibition of voltage-gated Na+ channels expressed in primary afferent neurons. In the present study, we examined whether NSAIDs modulate tetrodotoxin-resistant (TTX-R) Na+ channels and if this modulation depends on the extracellular pH. The TTX-R Na+ currents were recorded from small-sized trigeminal ganglion neurons by using a whole-cell patch clamp technique. Among eight NSAIDs tested in this study, several drugs, including aspirin and ibuprofen, did not affect TTX-R Na+ channels either at pH 7.4 or at pH 6.0. However, we found that indomethacin, and, to a lesser extent, ibuprofen and naproxen potently inhibited the peak amplitude of TTX-R Na+ currents at pH 6.0. The indomethacin-induced inhibition of TTX-R Na+ channels was more potent at depolarized membrane potentials. Indomethacin significantly shifted both the voltage activation and voltage-inactivation relationships to depolarizing potentials at pH 6.0. Indomethacin accelerated the development of inactivation and retarded the recovery from inactivation of TDC-R Na+ channels at pH 6.0. Given that indomethacin and several other NSAIDs could further suppress local nociceptive signals by inhibiting TTX-R Na+ channels at an acidic pH in addition to the classical COX inhibition, these drugs could be particularly useful for the treatment of inflammatory pain. (C) 2016 Elsevier Ltd. All rights reserved.