Axotomy-induced changes in activity-dependent slowing in peripheral nerve fibres: role of hyperpolarization-activated/HCN channel current.

摘要

Slowing refers to the gradual decrease in conduction velocity evoked by repetitive electrical stimuli. The underlying mechanisms are still poorly understood, and its physiological/pathological relevance scarcely discussed; however, changes in axonal conduction properties might unmask abnormal nociceptor function and alter the encoding time window at the spinal cord.Here, we characterized and compared the slowing in isolated units recorded from intact and axotomized saphenous nerves from mice, in vitro. We evaluated the role of hyperpolarization-activated/HCN channel current, Ih , in the generation of slowing, by examining the effect of the specific Ih blocker ZD7288.Based on their degree of slowing, intact C-fibres were classified as presumed nociceptors or non-nociceptors (>13% or <7% latency increase, respectively). Upon ZD7288 treatment, slowing was significantly augmented in 19/25 of the presumed C-nociceptors. In nerve-end neuromas, axotomized C-fibres could not be classified by their degree of slowing, which, in addition, was unrelated to the presence of ectopic mechanosensitivity. Axotomized fibres showed a ～2.5-fold reduction in their slowing as compared with intact units and the effects of ZD7288 were more prominent, both in magnitude and percentage of sensitive fibres. Interestingly, in control conditions, all fibres sensitive to ZD7288 were more resistant to slowing.Under our experimental conditions, slowing seems largely dependent on functional Ih . The marked decrease in slowing after axotomy in C-fibres fits with the increased expression of functional hyperpolarization-activated/HCN channel current and may underlie the analgesic effects of the specific Ih blocker ZD7288 previously described in neuropathic pain models.