Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States . Dr. Zhang is now with the Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Pain. 2021 May 1;162(5):1483-1499. doi: 10.1097/j.pain.0000000000002147.
A large body of animal and human studies indicates that blocking peripheral calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling pathways may prevent migraine episodes and reduce headache frequency. To investigate whether recurring migraine episodes alter the strength of CGRP and PACAP signaling in trigeminal ganglion (TG) neurons, we compared the number of TG neurons that respond to CGRP and to PACAP (CGRP-R and PACAP-R, respectively) under normal and chronic migraine-like conditions. In a mouse model of chronic migraine, repeated nitroglycerin (NTG) administration significantly increased the number of CGRP-R and PACAP-R neurons in TG but not dorsal root ganglia. In TG neurons that express endogenous αCGRP, repeated NTG led to a 7-fold increase in the number of neurons that respond to both CGRP and PACAP (CGRP-R&PACAP-R). Most of these neurons were unmyelinated C-fiber nociceptors. This suggests that a larger fraction of CGRP signaling in TG nociceptors may be mediated through the autocrine mechanism, and the release of endogenous αCGRP can be enhanced by both CGRP and PACAP signaling pathways under chronic migraine condition. The number of CGRP-R&PACAP-R TG neurons was also increased in a mouse model of posttraumatic headache (PTH). Interestingly, low-dose interleukin-2 treatment, which completely reverses chronic migraine-related and PTH-related behaviors in mouse models, also blocked the increase in both CGRP-R and PACAP-R TG neurons. Together, these results suggest that inhibition of both CGRP and PACAP signaling in TG neurons may be more effective in treating chronic migraine and PTH than targeting individual signaling pathways.
大量的动物和人体研究表明，阻断外周降钙素基因相关肽（CGRP）和垂体腺苷酸环化酶激活肽（PACAP）信号通路可能预防偏头痛发作并减少头痛频率。为了研究反复发作的偏头痛是否会改变三叉神经节（TG）神经元中 CGRP 和 PACAP 信号的强度，我们比较了正常和慢性偏头痛样条件下对 CGRP 和 PACAP 有反应的 TG 神经元的数量（分别为 CGRP-R 和 PACAP-R）。在慢性偏头痛的小鼠模型中，重复给予硝化甘油（NTG）显著增加了 TG 中 CGRP-R 和 PACAP-R 神经元的数量，但在背根神经节中没有增加。在表达内源性αCGRP 的 TG 神经元中，重复 NTG 导致对 CGRP 和 PACAP 均有反应的神经元数量增加了 7 倍（CGRP-R&PACAP-R）。这些神经元中的大多数是无髓 C 纤维伤害感受器。这表明 TG 伤害感受器中的 CGRP 信号的更大比例可能通过自分泌机制介导，并且在慢性偏头痛状态下，内源性αCGRP 的释放可以通过 CGRP 和 PACAP 信号通路增强。创伤后头痛（PTH）的小鼠模型中 CGRP-R&PACAP-R TG 神经元的数量也增加了。有趣的是，低剂量白细胞介素-2 治疗可完全逆转慢性偏头痛相关和 PTH 相关行为的小鼠模型，也阻断了 CGRP-R 和 PACAP-R TG 神经元的增加。总之，这些结果表明，抑制 TG 神经元中的 CGRP 和 PACAP 信号可能比针对单个信号通路更有效地治疗慢性偏头痛和 PTH。
