Enhancement of membrane K(+) conductance may reduce the abnormal excitability of primary afferent nociceptive neurons in neuropathic pain. It has been shown that retigabine, a novel anticonvulsant, activates Kv7 (KCNQ/M) channels in the axonal/nodal membrane of peripheral myelinated axons. In this study, we have tested the effects of retigabine on excitability parameters of C-type nerve fibers in isolated fascicles of human sural nerve. Application of retigabine (3-10 microM) produced an increase in membrane threshold. This effect was pronounced in depolarized axons and small in hyperpolarized axons. This finding indicates that retigabine produces a membrane hyperpolarization which is limited by the K(+) equilibrium potential. The retigabine-induced reduction in excitability was accompanied by modifications of the post-spike recovery cycle. Most notable is the development of a late subexcitability at 250-400 ms following a short burst of action potentials. All effects of retigabine were blocked in the presence of XE991 (10 microM). The data show that Kv7 channels are present on axons of unmyelinated, including nociceptive, peripheral human nerve fibers. It is likely that activation of these channels by retigabine may reduce the ectopic generation of action potentials in neuropathic pain.