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Expression of ASIC3 in the Trigeminal Nucleus Caudalis Plays a Role in a Rat Model of Recurrent Migraine

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Abstract

Acid-sensing ion channel 3 (ASIC3) is abundant in the trigeminal nervous system and is most sensitive to a slight pH decrease. Recent studies have indicated that ASIC3 in the peripheral trigeminal ganglia is likely involved in the pathogenesis of migraine pain. However, it is unclear whether this receptor plays a role in recurrent migraine, namely, migraine chronicity. Here, we aimed to investigate the role of ASIC3 in an animal model of recurrent migraine (RM). In this study, we established a rat model of RM through repeated administration of inflammatory soup (IS) onto the dura. Then, we tested the mechanical pain thresholds of the face and hindpaws by von Frey filaments. qRT-PCR, Western blot and immunofluorescence labelling were used to detect the expression and localization of ASIC3 in the trigeminal nucleus caudalis (TNC). The protein levels of calcitonin gene-related peptide (CGRP), its receptor component receptor activity modifying protein 1 (RAMP1) and c-Fos were analysed following treatment with the ASIC3 inhibitor APETx2 and activator 2-guanidine-4-methylquinazoline (GMQ). We found decreased pain thresholds after repeated dural inflammatory stimulation, which suggested the establishment of an RM model. Based on this model, we observed elevated expression of ASIC3 in the TNC group compared to that in the Sham group. ASIC3 was primarily expressed in neurons but not in astrocytes of the TNC. Moreover, APETx2 attenuated tactile allodynia and significantly decreased the expression of c-Fos, CGRP and RAMP1, while GMQ aggravated these effects compared to those observed in the IS + vehicle group. These findings indicate a critical role of ASIC3 channels in the pathophysiology of RM, and ASIC3 might represent a potential therapeutic target to prevent the progression of migraine.

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Abbreviations

ASIC3:

Acid-sensing ion channel 3

APETx2:

Anthopleura elegantissima

CGRP:

Calcitonin gene-related peptide

C2:

Cervical spinal 2

CNS:

Central nervous system

DMSO:

Dimethyl sulfoxide

GMQ:

2-Guanidine-4-methylquinazoline

IS:

Inflammatory soup

PBS:

Phosphate-buffered solution

PGE2:

Prostaglandin E2

qRT-PCR:

Quantitative real-time reverse transcription-polymerase chain reaction

RM:

Recurrent migraine

RAMP1:

Receptor activity modifying protein 1

SP:

Substance P

TNC:

Trigeminal nucleus caudalis

TRPV1:

Transient receptor potential vanilloid type 1

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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81671093 and 81500957) and the District Science and Technology Projects of Yuzhong Chongqing (No. 20160107).

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Authors and Affiliations

  1. Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Sha Wang, Bai-Xue Wu, Chao-Yang Liu, Guang-Cheng Qin, Wen-Hui Yan & Li-Xue Chen

  2. Chongqing Key Laboratory of Neurology, Chongqing, 400016, People’s Republic of China

    Ji-Ying Zhou

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  1. Sha Wang
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  2. Bai-Xue Wu
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Contributions

LXC and JYZ developed the experimental design. LXC, GCQ and WHY oversaw the experiments. SW, CYL and BXW performed the experiments. SW drafted the manuscript. LXC revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Li-Xue Chen.

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All experimental protocols were approved by the Ethics Committee of the Department of Medical Research (First Affiliated Hospital of Chongqing Medical University).

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The authors declare that they have no competing interests.

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Wang, S., Wu, BX., Liu, CY. et al. Expression of ASIC3 in the Trigeminal Nucleus Caudalis Plays a Role in a Rat Model of Recurrent Migraine. J Mol Neurosci 66, 44–52 (2018). https://doi.org/10.1007/s12031-018-1113-3

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