Analgesic effect of ivabradine against inflammatory pain mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels expressed on primary afferent terminals in the spinal dorsal horn

Ivabradine, a hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel blocker and clinically approved bradycardic agent, has analgesic effects against neuropathic pain. Although the expression of HCN channels in the spinal dorsal horn (SDH) is augmented under inflammatory pain, spinal responses to centrally and peripherally applied ivabradine remain poorly understood. We investigated the spinal action and cellular mechanisms underlying the drug's analgesic effects against inflammatory pain using inflammatory pain model rats. Intraperitoneal and intrathecal injections of ivabradine inhibited mechanical allodynia (6 rats/dose; P < 0.05), and immunohistochemical staining showed that ivabradine suppresses the phosphorylated extracellular signal-regulated kinase activation in the SDH (6 rats/group, P < 0.01). In vitro whole-cell patch-clamp and in vivo extracellular recordings showed that direct application of ivabradine to the spinal cord decreases the mean miniature excitatory postsynaptic currents' frequency (13 rats; P < 0.01), and direct and peripheral application of ivabradine suppresses the spinal response to mechanical stimulation-evoked firing (8 rats/group, P < 0.01). Moreover, ivabradine reduces the amplitudes of monosynaptic excitatory postsynaptic currents evoked by Aδ-fiber and C-fiber stimulation (6 rats; P < 0.01) and induces a stronger inhibition of those evoked by C-fiber stimulation. These phenomena were inhibited by forskolin, an activator of HCN channels. In conclusion, spinal responses mediated by HCN channels on primary afferent terminals are suppressed by central and peripheral administration of ivabradine; the drug also exhibits analgesic effects against inflammatory pain. In addition, ivabradine preferentially acts on C-fiber terminals of SDH neurons and induces a stronger inhibition of neuronal excitability in inflammatory pain.