Ivabradine reduces neuropathic pain after spinal cord injury by inhibiting excitatory synaptic transmission in the spinal dorsal horn

Nobuko Ohashi; Masayuki Ohashi; Rintaro Hoshino; Hiroyuki Deguchi; Hiroshi Baba

doi:10.1016/j.neulet.2025.138113

Ivabradine reduces neuropathic pain after spinal cord injury by inhibiting excitatory synaptic transmission in the spinal dorsal horn

Neurosci Lett. 2025 Jan 5:848:138113. doi: 10.1016/j.neulet.2025.138113. Online ahead of print.

Authors

Nobuko Ohashi¹, Masayuki Ohashi², Rintaro Hoshino³, Hiroyuki Deguchi³, Hiroshi Baba⁴

Affiliations

¹ Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan. Electronic address: ww81854@sa2.so-net.ne.jp.
² Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan. Electronic address: masayuki-ohashi@ksh.biglobe.ne.jp.
³ Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan.
⁴ Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan. Electronic address: baba@med.niigata-u.ac.jp.

PMID: 39765281
DOI: 10.1016/j.neulet.2025.138113

Abstract

Spinal cord injuries (SCIs) can lead to severe neuropathic pain and increased risk of myocardial infarction and heart failure; therefore, the use of analgesics against SCI-induced pain should be minimized because of their adverse effects on the cardiovascular system. Ivabradine, a blocker of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels, is used as a bradycardic agent, but recent studies focused on it as an analgesic agent for peripheral neuropathic pain. However, the analgesic effects of ivabradine on central neuropathic pain, such as SCI-induced pain, have not been examined. The aim of this study was to investigate the spinal analgesic effects of ivabradine on central neuropathic pain induced by SCI. Ivabradine induced analgesia in both spontaneous pain-related behavior and mechanical allodynia in SCI-induced pain (6-7 rats/group; p < 0.01). In immunohistochemical staining analyses, ivabradine suppressed phosphorylation of extracellular signal-regulated kinases activated by SCI-induced pain in the superficial spinal dorsal horn (6 rats/group; p < 0.01). In in vitro whole-cell patch-clamp analysis, ivabradine decreased the frequency of miniature excitatory postsynaptic currents in substantia gelatinosa neurons (11-12 rats/group; p < 0.01). We concluded that ivabradine reduces SCI-induced pain by inhibiting excitatory synaptic transmission in the spinal dorsal horn.

Keywords: Hyperpolarization-activated cyclic nucleotide-gated cation channel; Ivabradine; Neuropathic pain; Spinal cord injury; Spinal dorsal horn.