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Hyperpolarization‐activated channels shape temporal patterns of ectopic spontaneous discharge in C‐nociceptors after peripheral nerve injury
Author(s) -
Bernal L.,
Roza C.
Publication year - 2018
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.1226
Subject(s) - nociceptor , nociception , neuroscience , bursting , chemistry , hyperpolarization (physics) , hcn channel , ectopic expression , electrophysiology , biophysics , ion channel , biology , receptor , biochemistry , organic chemistry , nuclear magnetic resonance spectroscopy , gene
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, ZD 7288, significantly suppressed ectopic spontaneous discharges in nociceptive fibres (3/5 Aδ‐ and 24/31 C‐units and 1 nonclassified) by 64%. Additionally, ZD 7288 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 ZD 7288. In six additional fibres (three Clock‐like and three Irregular), exogenous cAMP had no further effect, but co‐application with ZD 7288 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.