Inhibition of the I(h) current in isolated peripheral nerve: a novel mode of peripheral antinociception?
Although the alpha2-adrenergic agonist clonidine has been shown to promote peripheral antinociception, its mechanism of action has not yet been clearly elucidated. By the use of the sucrose-gap method, we have shown that in C fibers of the rabbit vagus nerve, clonidine at micromolar concentrations enhances activity-dependent hyperpolarizations generated by the Na+-K+ pump during and after repetitive stimulation. Similar results were obtained with 10 microM of ZD 7288, a specific blocker of the hyperpolarization-activated cation current (I(h)) and with 2 mM of Ba2+ that blocks the inwardly rectifying potassium current (I(KIR)). Furthermore, clonidine had no added effect on the ZD 7288-induced response, whereas it produced a marked enhancement of Ba2+induced response. From these results, it can be concluded that clonidine enhances activity-dependent hyperpolarization by inhibiting the current I(h). We propose that clonidine, by increasing the threshold for initiating the action potential, induces a slowing or block of conduction and that this mechanism is the origin of the clonidine-induced antinociception. Finally, this study suggests a novel role for inwardly rectifying hyperpolarization-activated conductances in peripherally mediated antinociception.
Dalle
C
C
Département APSIC Pharmacologie, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Genève 4, Switzerland. carine.dalle@medecine.unige.ch
Schneider
M
M
Clergue
F
F
Bretton
C
C
Jirounek
P
P
D000200:Action Potentials / Q000187:drug effects; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009412:Nerve Fibers / Q000187:drug effects; D009413:Nerve Fibers, Myelinated / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D013395:Sucrose / Q000494:pharmacology; D014630:Vagus Nerve / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D002317:Cardiovascular Agents; D007473:Ion Channels; D011743:Pyrimidines; C082246:ICI D2788; D001464:Barium; D013395:Sucrose; D003000:Clonidine