PACAP inhibition alleviates neuropathic pain by modulating Nav1.7 through the MAPK/ERK signaling pathway in a rat model of chronic constriction injury

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM Neuropeptides Pub Date : 2023-06-01 DOI:10.1016/j.npep.2023.102327

Mingzheng Liu , Fan He , Mengci Shao , Tianyuan Li , Liecheng Wang , Yuanyin Wang , Wenhua Xu

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引用次数: 2

Abstract

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.

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在慢性收缩损伤大鼠模型中，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障碍，其病理可能与电压门控钠通道有关。先前的研究报道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，目的研究大鼠眶下神经慢性收缩损伤后，PACAP是否能通过有丝分裂原活化蛋白激酶/ERK激酶/细胞外信号调节激酶（MEK/ERK）途径调节三叉神经节的Nav1.7。研究设计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）。定量实时PCR和蛋白质印迹用于定量ATF3、PACAP、ERK、p-ERK和Nav1.7的表达。结果ION-CCI后第3天至第21天，机械痛阈下降，第14天达到最低检测值；然而，在PACAP 6-38和PD98059注射后，它增加了。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；ERK的表达没有差异。PACAP 6–38注射液显著降低了PACAP、p-ERK和Nav1.7的表达，并增加了PAC1受体的表达，而ERK的表达没有变化。此外，PD98059注射液降低了PACAP、p-ERK和Nav1.7的表达，并增加了PAC1受体的表达。结论ION-CCI后，大鼠三叉神经节的PACAP可通过PAC1受体通过MEK/ERK通路调节Nav1.7。此外，PACAP抑制减轻了ION-CCI大鼠的异常性疼痛。

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来源期刊

Neuropeptides 医学-内分泌学与代谢

CiteScore

5.40

自引率

6.90%

发文量

审稿时长

>12 weeks

期刊介绍： The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.