Celecoxib inhibits Na+ currents in rat dorsal root ganglion neurons.
Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used in the treatment of osteoarthritis and rheumatoid arthritis with fewer gastrointestinal toxicities compared to traditional non-steroidal anti-inflammatory drugs. Voltage-gated Na(+) channels in primary sensory neurons play an important role in the pathogenesis of various pain conditions. We examined the effects of celecoxib on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na(+) currents in acutely dissociated rat dorsal root ganglion neurons. Celecoxib suppressed both currents in dose- and frequency-dependent manner. The apparent dissociation constants (K(d)) for TTX-S and TTX-R Na(+) currents measured at 0 mV from a holding potential of -80 mV were estimated to be 5.6 and 19.5 microM, respectively. Celecoxib slightly slowed inactivation kinetics of TTX-S Na(+) current, but made it much faster in TTX-R Na(+) current. Celecoxib shifted the activation voltage of TTX-S Na(+) current to a depolarizing direction, but not that of TTX-R Na(+) current. Celecoxib caused a hyperpolarizing shift of the steady-state inactivation curve in both Na(+) currents to a great extent. In addition celecoxib reduced the maximal availability of both Na(+) channels. Thus celecoxib appears to bind to both inactivated and resting Na(+) channels. Celecoxib slowed the recovery of both Na(+) channels from inactivation. All these effects combined would suppress the excitability of sensory neurons. Thus, beside COX-2 inhibition, the Na(+) channel inhibition is considered to contribute to celecoxib analgesia.
Park
Soon Yong
SY
Department of Pharmacology, Chung-Ang University, College of Medicine, 221 Heuksuk-Dong, Dongjak-Ku, Seoul 156-756, Republic of Korea.
Kim
Tae Hoon
TH
Kim
Hong Im
HI
Shin
Yong Kyoo
YK
Lee
Chung Soo
CS
Park
Mijung
M
Song
Jin-Ho
JH
D000818:Animals; D000831:Animals, Newborn; D000068579:Celecoxib; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013449:Sulfonamides; D013779:Tetrodotoxin; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000068579:Celecoxib