Ketamine blockage of both tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels of rat dorsal root ganglion neurons.
Ketamine, a general anesthetic, has been reported to block sodium channels. Two types of Na(+) channels, tetrodotoxin (TTX)-sensitive (TTX-s) and TTX-resistant (TTX-r), are expressed in dorsal root ganglion (DRG) neurons. The present study was to investigate the effects of ketamine on both types, particularly on TTX-r channels, using whole-cell patch-clamp recordings in dissociated rat DRG neurons. In addition to confirming ketamine-induced blockage of TTX-s Na(+) current, we showed for the first time that ketamine blocked TTX-r Na(+) channels on small DRG neurons in dose-dependent and use-dependent manner. Half-maximal inhibitory concentration (IC(50)) was 866.2 microM for TTX-r Na(+) channels. TTX-r Na(+) channels were more sensitive to ketamine in inactivated state (IC(50) = 314.8 microM) than in resting state (IC(50) = 866.2 microM). IC(50) was 146.7 microM for TTX-s Na(+) current. Activation and inactivation properties of both TTX-s and TTX-r Na(+) channels were affected by ketamine. Since TTX-r Na(+) channels were preferentially expressed in small DRG neurons known as nociceptors, blockage of TTX-r Na(+) channels by ketamine may result in reducing nociceptive signals conducting to the spinal cord. Moreover, both TTX-r and TTX-s Na(+) channels would be non-selectively blocked by ketamine at high concentration, suggesting that the high dose of ketamine might produce an action of local anesthesia.
Zhou
Z S
ZS
Shanghai Institute of Physiology, Chinese Academy of Sciences, P. R., Shanghai, China.
Zhao
Z Q
ZQ
D000200:Action Potentials / Q000187:drug effects; D000778:Anesthetics, Dissociative / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002469:Cell Separation; D048429:Cell Size; D004305:Dose-Response Relationship, Drug; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology*
D000778:Anesthetics, Dissociative; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D007649:Ketamine; D012964:Sodium; D002211:Capsaicin