BACKGROUND: Peripheral nerve injury increases the excitability of primary sensory neurons. This triggers the onset of neuropathic pain and maintains its persistence. Because changes in hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are implicated in this process, we examined the action of the heart-rate-reducing agent, ivabradine, a clinically approved HCN blocker, in the rat chronic constriction injury (CCI) model of neuropathic pain. METHODS: The effects of ivabradine on mechanical allodynia were assessed using von Frey filaments, and the effects on cardiovascular parameters were monitored by telemetry. Ivabradine block of HCN channels in dorsal root ganglion neurons was confirmed by whole-cell recording. RESULTS: In rats subject to CCI, ivabradine (6 mg/kg by gavage twice a day) significantly reduced mechanical allodynia. Cumulative effects were seen with twice daily oral administration over a 4-day period. Allodynia returned 4 days after the final drug dose. Mean arterial pressure was maintained and only a 15% pharmacological reduction in heart rate was observed. There was no cumulative effect of ivabradine on cardiovascular parameters. CONCLUSION: Because ivabradine is effective at an oral dose that produces only moderate pharmacological heart rate reduction, and this is known to be well tolerated in a clinical context, these results underline its possible use in neuropathic pain management.
BACKGROUND: Peripheral nerve injury increases the excitability of primary sensory neurons. This triggers the onset of neuropathic pain and maintains its persistence. Because changes in hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are implicated in this process, we examined the action of the heart-rate-reducing agent, ivabradine, a clinically approved HCN blocker, in the rat chronic constriction injury (CCI) model of neuropathic pain. METHODS: The effects of ivabradine on mechanical allodynia were assessed using von Frey filaments, and the effects on cardiovascular parameters were monitored by telemetry. Ivabradine block of HCN channels in dorsal root ganglion neurons was confirmed by whole-cell recording. RESULTS: In rats subject to CCI, ivabradine (6 mg/kg by gavage twice a day) significantly reduced mechanical allodynia. Cumulative effects were seen with twice daily oral administration over a 4-day period. Allodynia returned 4 days after the final drug dose. Mean arterial pressure was maintained and only a 15% pharmacological reduction in heart rate was observed. There was no cumulative effect of ivabradine on cardiovascular parameters. CONCLUSION: Because ivabradine is effective at an oral dose that produces only moderate pharmacological heart rate reduction, and this is known to be well tolerated in a clinical context, these results underline its possible use in neuropathic pain management.
Authors: Rebecca L Joyce; Nicole P Beyer; Georgia Vasilopoulos; Kellie A Woll; Adam C Hall; Roderic G Eckenhoff; Dipti N Barman; J David Warren; Gareth R Tibbs; Peter A Goldstein Journal: Biochem Pharmacol Date: 2019-02-13 Impact factor: 5.858
Authors: Christoforos Tsantoulas; Sergio Laínez; Sara Wong; Ishita Mehta; Bruno Vilar; Peter A McNaughton Journal: Sci Transl Med Date: 2017-09-27 Impact factor: 17.956
Authors: Han-Shen Tae; Kelly M Smith; A Marie Phillips; Kieran A Boyle; Melody Li; Ian C Forster; Robert J Hatch; Robert Richardson; David I Hughes; Brett A Graham; Steven Petrou; Christopher A Reid Journal: Front Pharmacol Date: 2017-08-21 Impact factor: 5.810
Authors: Leonardo Dini; Martina Del Lungo; Francesco Resta; Michele Melchiorre; Valentina Spinelli; Lorenzo Di Cesare Mannelli; Carla Ghelardini; Annunziatina Laurino; Laura Sartiani; Raffaele Coppini; Guido Mannaioni; Elisabetta Cerbai; Maria Novella Romanelli Journal: Front Pharmacol Date: 2018-11-08 Impact factor: 5.810