title: Indomethacin inhibits tetrodotoxin-resistant Na(+) channels at acidic pH in rat nociceptive neurons.
abstract: 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 TTX-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.
authors.affiliation: Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 700-412, Republic of Korea; Brain Science & Engineering Institute, Kyungpook National University, Daegu 700-412, Republic of Korea.
authors.forename: Michiko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 700-412, Republic of Korea; Brain Science & Engineering Institute, Kyungpook National University, Daegu 700-412, Republic of Korea. Electronic address: jis7619@knu.ac.kr.
authors.forename: Il-Sung
authors.initials: IS
authors.lastname: Jang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D006863:Hydrogen-Ion Concentration; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009288:Naproxen / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015222:Sodium Channels; D009288:Naproxen; D001241:Aspirin; D007052:Ibuprofen; D007213:Indomethacin
keywords: Indomethacin; Inflammatory pain; NSAID; Patch clamp; TTX-R Na(+) channels; Trigeminal ganglia