Effects of alpha2-adrenoceptor agonists on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglion neurons.
OBJECTIVE
When intrathecally or epidurally administered, alpha2-adrenoceptor agonists produce potent antinociception by affecting the activity of primary afferent fibres and spinal cord neurons. Recent reports have indicated that in dorsal root ganglion neurons, tetrodotoxin-resistant Na+ channels play important roles in the conduction of nociceptive sensation. We therefore investigated the effects of alpha2-adrenoceptor agonists on tetrodotoxin-resistant Na+ currents.


METHODS
Using the whole-cell patch-clamp technique, we recorded tetrodotoxin-resistant Na+ currents from rat dorsal root ganglion neurons.


RESULTS
Both clonidine and dexmedetomidine reduced the peak amplitude of the tetrodotoxin-resistant Na+ current concentration- and use-dependently. The concentration required for a half-maximal effect was significantly lower for dexmedetomidine (58.0 +/- 10.2 micromol) than for clonidine (257.2 +/- 30.9 micromol) at holding potential -70 mV. The current inhibitions induced by these agonists were not prevented by 1 micromol yohimbine, an alpha2-adrenoceptor antagonist. Both clonidine and dexmedetomidine shifted the inactivation curve for the tetrodotoxin-resistant Na+ current in the hyperpolarizing direction. The combinations clonidine with lidocaine and dexmedetomidine with lidocaine produced an additive blockade-type interaction on the tetrodotoxin-resistant Na+ current.


CONCLUSIONS
The results suggest that a direct inhibition of tetrodotoxin-resistant Na+ channels may contribute to the antinociceptive effects of clonidine and dexmedetomidine when used as additives to regional anaesthesia.
Oda
A
A
Gifu University Graduate School of Medicine, Department of Anesthesiology and Pain Medicine, Gifu, Japan.
Iida
H
H
Tanahashi
S
S
Osawa
Y
Y
Yamaguchi
S
S
Dohi
S
S
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000465:Algorithms; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D020927:Dexmedetomidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000008:administration & dosage*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000779:Anesthetics, Local; D018341:Receptors, Adrenergic, alpha-2; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D015016:Yohimbine; D013779:Tetrodotoxin; D020927:Dexmedetomidine; D008012:Lidocaine; D003000:Clonidine