Inhibition of the I _h current in isolated peripheral nerve: A novel mode of peripheral antinociception?

Abstract

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.