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Published on: March 21, 2025
Hyperpolarization-activated channels shape temporal patterns of ectopic spontaneous discharge in C-nociceptors after
1Department of Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
Background:
Neuropathic 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.
Methods:
We 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.
Results:
Both 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.
Conclusions:
Our 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.
Significance:
We 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.
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