Article (Scientific journals)
Selective blockade of HCN1/HCN2 channels as a potential pharmacological strategy against pain
Dini, Leonardo; Del Lungo, Martina; Resta, Francesco et al.
2018In Frontiers in Pharmacology, 9, p. 1252
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Keywords :
Dorsal root ganglion neurons; HCN channel blockade; Hyperpolarization-activated current; Neuropathic pain; Oxaliplatin
Abstract :
[en] A prominent role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels has been suggested based on their expression and (dys)function in dorsal root ganglion (DRG) neurons, being likely involved in peripheral nociception. Using HCN blockers as antinociceptive drugs is prevented by the widespread distribution of these channels. However, tissue-specific expression of HCN isoforms varies significantly, HCN1 and HCN2 being considered as major players in DRG excitability. We characterized the pharmacological effect of a novel compound, MEL55A, able to block selectively HCN1/HCN2 isoforms, on DRG neuron excitability in-vitro and for its antiallodynic properties in-vivo. HEK293 cells expressing HCN1, HCN2, or HCN4 isoforms were used to verify drug selectivity. The pharmacological profile of MEL55A was tested on mouse DRG neurons by patch-clamp recordings, and in-vivo in oxaliplatin-induced neuropathy by means of thermal hypersensitivity. Results were compared to the non-isoform-selective drug, ivabradine. MEL55A showed a marked preference toward HCN1 and HCN2 isoforms expressed in HEK293, with respect to HCN4. In cultured DRG, MEL55A reduced h amplitude, both in basic conditions and after stimulation by forskolin, and cell excitability, its effect being quantitatively similar to that observed with ivabradine. MEL55A was able to relieve chemotherapy-induced neuropathic pain. In conclusion, selective blockade of HCN1/HCN2 channels, over HCN4 isoform, was able to modulate electrophysiological properties of DRG neurons similarly to that reported for classical Ih blockers, ivabradine, resulting in a pain-relieving activity. The availability of small molecules with selectivity toward HCN channel isoforms involved in nociception might represent a safe and effective strategy against chronic pain.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Dini, Leonardo;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Del Lungo, Martina;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Resta, Francesco;  European Laboratory of Non Linear Spectroscopy, Florence, Italy
Melchiorre, Michele ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Physics and Materials Science Research Unit
Spinelli, Valentina;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Di Cesare Mannelli, Leonardo;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Ghelardini, Carla;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Laurino, Annunziatina;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Sartiani, Laura;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Coppini, Raffaele;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Mannaioni, Guido;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Cerbai, Elisabetta;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
Romanelli, Maria Novella;  University of Florence, Florence, Italy > Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa)
More authors (3 more) Less
External co-authors :
yes
Language :
English
Title :
Selective blockade of HCN1/HCN2 channels as a potential pharmacological strategy against pain
Publication date :
08 November 2018
Journal title :
Frontiers in Pharmacology
ISSN :
1663-9812
Publisher :
Frontiers Media S.A., Switzerland
Volume :
9
Pages :
1252
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 20 November 2018

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