Yamamoto Shohei, Suzuki Yuma, Ono Hideki, Kume Kazuhiko, Ohsawa Masahiro
Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan; Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan.
Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan.
Eur J Pharmacol. 2016 Dec 15;793:66-75. doi: 10.1016/j.ejphar.2016.11.001. Epub 2016 Nov 5.
Cilnidipine is a dihydropyridine derivative that inhibits N-type and L-type voltage-gated Ca channels (VDCCs). We recently reported that a selective N-type VDCC blocker attenuated the spinal long-term potentiation (LTP) of C-fiber-evoked field potentials recorded in the spinal dorsal horn of rats, which served as a model for examining synaptic function during central pain sensitization. In this study, we investigated the effects of cilnidipine on the changes related to neuropathic pain induced by nerve injury. Mechanical allodynia and hyperalgesia were evaluated by von Frey test and pin prick test, respectively. Spinal LTP of C-fiber-evoked field potentials were evaluated by in vivo electrophysiology. Intrathecally administrated cilnidipine attenuated mechanical allodynia and hyperalgesia in the spared nerve injury mouse model. Using in vivo electrophysiology in rats, cilnidipine (10µm) administered spinally inhibited the induction and maintenance of high-frequency stimulation-induced LTP of C-fiber-evoked field potentials, while basal C-fiber-evoked field potentials in naïve rats were unaffected. The basal C-fiber-evoked field potentials in nerve-injured rats were strongly inhibited by cilnidipine. Treatment with a specific N-type VDCC blocker, ω-conotoxin GVIA, which reportedly attenuates C-fiber-evoked field potentials both before and after the induction of LTP, attenuated mechanical allodynia and hyperalgesia in nerve-injured mice. By contrast, an L-type VDCC blocker, nicardipine attenuated only mechanical hyperalgesia, but not mechanical allodynia in nerve-injured mice, and also attenuated the established LTP of C-fiber-evoked field potentials in rats. These results suggested that N-type and L-type VDCC blockers may effectively alleviate the hyperalgesia and allodynia associated with neuropathic pain without affecting normal pain perception.
西尼地平是一种二氢吡啶衍生物，可抑制N型和L型电压门控钙通道（VDCCs）。我们最近报道，一种选择性N型VDCC阻滞剂可减弱在大鼠脊髓背角记录的C纤维诱发场电位的脊髓长时程增强（LTP），这作为在中枢性疼痛敏化过程中检查突触功能的模型。在本研究中，我们研究了西尼地平对神经损伤诱导的神经性疼痛相关变化的影响。分别通过von Frey试验和针刺试验评估机械性异常性疼痛和痛觉过敏。通过体内电生理学评估C纤维诱发场电位的脊髓LTP。鞘内注射西尼地平可减轻 spared 神经损伤小鼠模型中的机械性异常性疼痛和痛觉过敏。使用大鼠体内电生理学方法，脊髓注射西尼地平（10µm）可抑制高频刺激诱导的C纤维诱发场电位LTP的诱导和维持，而未处理大鼠的基础C纤维诱发场电位不受影响。西尼地平强烈抑制神经损伤大鼠的基础C纤维诱发场电位。用一种特异性N型VDCC阻滞剂ω-芋螺毒素GVIA治疗，据报道该阻滞剂可在LTP诱导之前和之后减弱C纤维诱发场电位，可减轻神经损伤小鼠的机械性异常性疼痛和痛觉过敏。相比之下，L型VDCC阻滞剂尼卡地平仅减轻神经损伤小鼠的机械性痛觉过敏，而不减轻机械性异常性疼痛，并且还减弱大鼠中已建立的C纤维诱发场电位LTP。这些结果表明，N型和L型VDCC阻滞剂可有效减轻与神经性疼痛相关的痛觉过敏和异常性疼痛，而不影响正常的疼痛感知。
