title: Inflammatory and neuropathic pain are rapidly suppressed by peripheral block of hyperpolarisation-activated cyclic nucleotide-gated ion channels.
abstract: Previous studies have shown that hyperpolarisation-activated cyclic nucleotide-gated (HCN)-2 ion channels regulate the firing frequency of nociceptive sensory neurons and thus play a central role in both inflammatory and neuropathic pain conditions. Here we use ivabradine, a clinically approved anti-anginal agent that blocks all HCN channel isoforms approximately equally, to investigate the effect on inflammatory and neuropathic pain of HCN ion channel block. We show that ivabradine does not have major off-target effects on a sample group of Na, Ca, and K ion channels, and that it is peripherally restricted because it is a substrate for the P-glycoprotein (PgP) multidrug transporter that is expressed in the blood-brain barrier. Its effects are therefore likely to be due to an action on HCN ion channels in peripheral sensory neurons. Using patch clamp electrophysiology, we found that ivabradine was a use-dependent blocker of native HCN channels expressed in small sensory neurons. Ivabradine suppressed the action potential firing that is induced in nociceptive neurons by elevation of intracellular cAMP. In the formalin model of inflammatory pain, ivabradine reduced pain behaviour only in the second (inflammatory) phase. In nerve injury and chemotherapy models of neuropathic pain, we observed rapid and effective analgesia as effective as that with gabapentin. We conclude that both inflammatory and neuropathic pain are rapidly inhibited by blocking HCN-dependent repetitive firing in peripheral nociceptive neurons.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK Wolfson Centre for Age-Related Research, King's College London, Guy's Campus, London Bridge, London, UK.
authors.forename: Gareth T
authors.initials: GT
authors.lastname: Young
authors.forename: Edward C
authors.initials: EC
authors.lastname: Emery
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Mooney
authors.forename: Christoforos
authors.initials: C
authors.lastname: Tsantoulas
authors.forename: Peter A
authors.initials: PA
authors.lastname: McNaughton
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D000077550:Ivabradine; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques
chemical_list: D001552:Benzazepines; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D000077550:Ivabradine
keywords: HCN ion channel; Inflammatory pain; Ion channel blocker; Neuropathic pain; Primary sensory neuron