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.

伊伐布雷定是一种超极化激活的环核苷酸门控阳离子 (HCN) 通道阻滞剂和临床批准的心动过缓剂，对神经性疼痛具有镇痛作用。尽管在炎症性疼痛下脊髓背角 (SDH) 中 HCN 通道的表达增强，但脊柱对中央和外周应用伊伐布雷定的反应仍然知之甚少。我们使用炎症性疼痛模型大鼠研究了药物对炎症性疼痛的镇痛作用的脊柱作用和细胞机制。腹膜内和鞘内注射伊伐布雷定抑制机械性异常性疼痛（6只大鼠/剂量；P< 0.05），免疫组织化学染色显示伊伐布雷定抑制 SDH 中磷酸化的细胞外信号调节激酶活化（6 只大鼠/组，P < 0.01）。体外全细胞膜片钳和体内细胞外记录表明，将伊伐布雷定直接应用到脊髓降低了平均微型兴奋性突触后电流的频率（13 只大鼠；P < 0.01），并且伊伐布雷定的直接和外周应用抑制了脊髓对机械刺激诱发放电的反应（8 只大鼠/组，P < 0.01）。此外，伊伐布雷定降低了由 Aδ 纤维和 C 纤维刺激引起的单突触兴奋性突触后电流的幅度（6 只大鼠；P< 0.01) 并诱导更强的抑制 C 纤维刺激引起的那些。这些现象被 HCN 通道的激活剂毛喉素抑制。总之，初级传入末端 HCN 通道介导的脊髓反应被伊伐布雷定的中枢和外周给药抑制；该药物还具有抗炎性疼痛的镇痛作用。此外，伊伐布雷定优先作用于 SDH 神经元的 C 纤维末端，并在炎症性疼痛中诱导更强的神经元兴奋性抑制。