Background

Trigeminal neuralgia is a common chronic maxillofacial neuropathic pain disorder, and voltage-gated sodium channels (VSGCs) are likely involved in its pathology. Prior studies report that pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide highly expressed in the trigeminal ganglion, may contribute to dorsal root ganglion neuron excitability by modulating the Nav1.7.

Objective

We investigated whether PACAP can regulate Nav1.7 through the mitogen-activated protein kinase/ERK kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway in the trigeminal ganglion after chronic constriction injury of the infraorbital nerve (ION-CCI) in rats.

Study design

Sprague-Dawley rats underwent ION-CCI, followed by intrathecal injection of PACAP 6–38 (PAC1 receptor antagonist) and PD98059 (MEK/ERK antagonist). Quantitative real-time PCR and western blot were used to quantify ATF3, PACAP, ERK, p-ERK, and Nav1.7 expression.

Results

The mechanical pain threshold decreased from day 3 to day 21 after ION-CCI and reached the lowest testing value by day 14; however, it increased after PACAP 6–38 and PD98059 injections. Additionally, ION-CCI surgery increased ATF3, PACAP, and p-ERK expression in the rat trigeminal ganglion and decreased Nav1.7 and PAC1 receptor expression; however, there was no difference in ERK expression. PACAP 6–38 injection significantly decreased PACAP, p-ERK, and Nav1.7 expression and increased the PAC1 receptor expression, with no change in ERK expression. Moreover, PD98059 injection decreased PACAP, p-ERK, and Nav1.7 expression and increased the expression of PAC1 receptor.

Conclusion

After ION-CCI, PACAP in the rat trigeminal ganglion can modulate Nav1.7 through the MEK/ERK pathway via the PAC1 receptor. Further, PACAP inhibition alleviates allodynia in ION-CCI rats.

中文翻译：

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在慢性压迫性损伤大鼠模型中，PACAP 抑制通过 MAPK/ERK 信号通路调节 Nav1.7 减轻神经性疼痛

背景

三叉神经痛是一种常见的慢性颌面部神经性疼痛疾病，电压门控钠通道 (VSGCs) 可能参与其病理。先前的研究报告称，垂体腺苷酸环化酶激活多肽 (PACAP) 是一种在三叉神经节中高度表达的神经肽，可能通过调节 Nav1.7 促进背根神经节神经元的兴奋性。

客观的

我们研究了 PACAP 是否可以通过眶下神经慢性压迫性损伤 (ION-CCI) 后三叉神经节中的丝裂原活化蛋白激酶/ERK 激酶/细胞外信号调节激酶 (MEK/ERK) 通路调节 Nav1.7老鼠。

学习规划

Sprague-Dawley 大鼠接受 ION-CCI，然后鞘内注射 PACAP 6-38（PAC1 受体拮抗剂）和 PD98059（MEK/ERK 拮抗剂）。使用定量实时 PCR 和蛋白质印迹来量化 ATF3、PACAP、ERK、p-ERK 和 Nav1.7 的表达。

结果

ION-CCI后第3天至第21天机械性痛阈下降，第14天达到最低检测值；然而，它在 PACAP 6-38 和 PD98059 注射后增加。此外，ION-CCI 手术增加了大鼠三叉神经节中 ATF3、PACAP 和 p-ERK 的表达，并降低了 Nav1.7 和 PAC1 受体的表达；然而，ERK 表达没有差异。PACAP 6-38 注射显着降低 PACAP、p-ERK 和 Nav1.7 表达并增加 PAC1 受体表达，而 ERK 表达没有变化。此外，PD98059 注射液可降低 PACAP、p-ERK 和 Nav1.7 的表达并增加 PAC1 受体的表达。

结论

在 ION-CCI 之后，大鼠三叉神经节中的 PACAP 可以通过 PAC1 受体通过 MEK/ERK 通路调节 Nav1.7。此外，PACAP 抑制可减轻 ION-CCI 大鼠的异常性疼痛。