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

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.

Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain

“…Importantly, ASIC3 is potentiated by NO donors and nitroglycerin (NTG) increases acid‐evoked pain in humans (Cadiou et al, ). In agreement with a role for ASICs in migraine, we and others have previously identified the anti‐migraine efficacy of targeting specific ASICs in several validated preclinical models (Holland et al, ; Verkest et al, ; Wang et al, ; Yan et al, ).…”

“…Specific ASIC1 blockade further inhibited cortical spreading depression propagation that we did not observe in the current study, likely due limited blood–brain barrier penetrability of APETx2, suggesting that the ASIC3‐mediated effects are likely peripheral at the level of the trigeminal afferents (Yan et al, ). Although specific central effects cannot be ruled out as ASIC3 is expressed centrally, including in the hypothalamus (Meng, Wang, Chen, Xu, & Zhou, ) and trigeminal nucleus caudalis, where its expression is up‐regulated in a dural‐inflammatory mediated preclinical model of migraine (Wang et al, ). In agreement with the potential efficacy of targeting ASIC signalling for migraine, it has recently been demonstrated that specific blockade of the ASIC1 subunit can inhibit NO‐evoked cutaneous allodynia in rats (Verkest et al, ), which supports our data and suggests that NO‐mediated attack triggering may have important central and peripheral actions on ASICs.…”

“…Given the emerging role for ASICs in migraine (Karsan, Gonzales, & Dussor, ), the expression of ASIC3 in the trigeminal ganglion (Ichikawa & Sugimoto, ) and the trigeminal nucleus caudalis (TNC; Wang et al, ) along with the enhancement of ASIC3 activity by NO donors (Cadiou et al, ), we sought to determine the role of ASIC3 in migraine and further determine if NO‐induced hyperalgesia may be in part ASIC3‐dependent. We report that durovascular‐evoked and NO‐induced sensitisation of trigeminal nociceptive responses in the trigeminal nucleus caudalis are inhibited by ASIC3 blockade.…”

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“…The migraine rat model in our study was similar to that employed in previous studies, [15][16][17][22][23][24][25] where IS was applied to produce a significant and stable reduction of the cutaneous receptive field pain threshold by activating the trigeminovascular system. Interestingly, this effect shows no bilateral facial difference.…”

“…Otherwise, a dural inflammatory soup (IS) injection is used to initiate migraine attacks and induce hyperalgesia and allodynia in the receptive field of the periorbital region of trigeminal nerve, using mechanical pain threshold test with a Von-Frey filament. 15,[22][23][24][25] Mechanical CCH may develop solely within the periorbital region and may spread throughout the face, scalp, limbs, and body. In addition to this, mechanical stimulation can induce skin pain, including hyperresponsiveness and hypersensitivity, which is either accompanied by a migraine attack or is interictal to it.…”