• L Bernal and C Roza.
• Department of Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
• Eur J Pain. 2018 Apr 10.

BackgroundNeuropathic pain is thought to be mediated by aberrant impulses from sensitized primary afferents, and the temporal summation of the discharges might also influence nociceptive processing. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Ih current) generate rhythmic activity in neurons within the central nervous system and contribute to nociceptors excitability in neuropathic pain.MethodsWe searched for single fibres with ectopic spontaneous discharges from an in vitro preparation in mice containing a neuroma formed in a peripheral branch of the saphenous nerve together with the undamaged branches.ResultsBoth damaged (axotomized) and undamaged fibres (putative intact) developed ectopic spontaneous activity with different temporal spike trains: Clock-like, Irregular or Bursts. The Ih current blocker, ZD7288, significantly suppressed ectopic spontaneous discharges in nociceptive fibres (3/5 Aδ- and 24/31 C-units and 1 nonclassified) by 64%. Additionally, ZD7288 changed the spike patterns of 5/7 Clock-like and 3/4 Burst units to Irregular. Exogenous cAMP produced a significant ~65% increase in the ectopic firing in 5 Irregular fibres, which was restored by ZD7288. In six additional fibres (three Clock-like and three Irregular), exogenous cAMP had no further effect, but co-application with ZD7288 decreased their discharge by half. These units showed significant higher levels of discharges than the cAMP-sensitive ones.ConclusionsOur data suggest that HCN channels modulate ectopic spontaneous firing in C-nociceptors and shape their temporal patterns of discharge which will, ultimately, modify the nociceptive message received and processed by second-order neurons.SignificanceWe show an involvement of HCN channels in the modulation of ectopic spontaneous discharges from C-nociceptors. This finding exposes a mechanism of nociceptive transmission enhancement and highlights the clinical relevance of peripheral HCN blockade for spontaneous pain relief during neuropathy.© 2018 European Pain Federation - EFIC®.

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