Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.
Department of Physiology & Biophysics, University of Washington, Seattle, WA 98125, USA.
Int J Mol Sci. 2021 Apr 6;22(7):3794. doi: 10.3390/ijms22073794.
The neuromodulator calcitonin gene-related peptide (CGRP) is known to facilitate nociceptive transmission in the superficial laminae of the spinal trigeminal nucleus caudalis (Sp5C). The central effects of CGRP in the Sp5C are very likely to contribute to the activation of central nociceptive pathways leading to attacks of severe headaches like migraine. To examine the potential impacts of CGRP on laminae I/II neurons at cellular and synaptic levels, we performed whole-cell patch-clamp recordings in juvenile mouse brainstem slices. First, we tested the effect of CGRP on cell excitability, focusing on neurons with tonically firing action potentials upon depolarizing current injection. CGRP (100 nM) enhanced tonic discharges together with membrane depolarization, an excitatory effect that was significantly reduced when the fast synaptic transmissions were pharmacologically blocked. However, CGRP at 500 nM was capable of exciting the functionally isolated cells, in a nifedipine-sensitive manner, indicating its direct effect on membrane intrinsic properties. In voltage-clamped cells, 100 nM CGRP effectively increased the frequency of excitatory synaptic inputs, suggesting its preferential presynaptic effect. Both CGRP-induced changes in cell excitability and synaptic drives were prevented by the CGRP receptor inhibitor BIBN 4096BS. Our data provide evidence that CGRP increases neuronal activity in Sp5C superficial laminae by dose-dependently promoting excitatory synaptic drive and directly enhancing cell intrinsic properties. We propose that the combination of such pre- and postsynaptic actions of CGRP might underlie its facilitation in nociceptive transmission in situations like migraine with elevated CGRP levels.
神经调质降钙素基因相关肽（CGRP）已知可促进三叉神经脊束核尾侧亚核（Sp5C）浅层的伤害性传递。CGRP 在 Sp5C 中的中枢效应很可能有助于激活中枢伤害性通路，导致偏头痛等严重头痛发作。为了研究 CGRP 在细胞和突触水平上对 I/II 层神经元的潜在影响，我们在幼年小鼠脑干切片上进行了全细胞膜片钳记录。首先，我们测试了 CGRP 对细胞兴奋性的影响，重点关注在去极化电流注入时具有持续放电动作电位的神经元。CGRP（100 nM）增强了持续放电和膜去极化，当快速突触传递被药理学阻断时，这种兴奋作用显著降低。然而，500 nM 的 CGRP 能够以硝苯地平敏感的方式兴奋功能上分离的细胞，表明其对膜内在特性的直接作用。在电压钳制细胞中，100 nM 的 CGRP 有效增加了兴奋性突触输入的频率，表明其优先的突触前作用。CGRP 受体抑制剂 BIBN 4096BS 可防止 CGRP 诱导的细胞兴奋性变化和突触驱动。我们的数据提供了证据，表明 CGRP 通过剂量依赖性地促进兴奋性突触驱动和直接增强细胞内在特性来增加 Sp5C 浅层神经元的活性。我们提出，CGRP 的这种前后突触作用的组合可能是其在偏头痛等 CGRP 水平升高情况下促进伤害性传递的基础。
