Abstract
BackgroundAccording to our previous study, microglia P2X4 receptors (P2X4Rs) play a pivotal role in the central sensitization of chronic migraine (CM). However, the molecular mechanism that underlies the crosstalk between microglia P2X4Rs and neurons of the trigeminal nucleus caudalis (TNC) is not fully understood. Therefore, the aim of this study is to examine the exact P2X4Rs signalling pathway in the development of central sensitization in a CM animal model.MethodsWe used an animal model with recurrent intermittent administration of nitroglycerin (NTG), which closely mimics CM. NTG-induced basal mechanical and thermal hypersensitivity were evaluated using a von Frey filament test and an increasing-temperature hot plate apparatus (IITC). We detected P2X4Rs, brain-derived neurotrophic factor (BDNF) and phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK) expression profiles in the TNC. We investigated the effects of a P2X4R inhibitor (5-BDBD) and an agonist (IVM) on NTG-induced hyperalgesia and neurochemical changes as well as on the expression of p-p38-MAPK and BDNF. We also detected the effects of a tropomyosin-related kinase B (TrkB) inhibitor (ANA-12) on the CM animal model in vivo. Then, we evaluated the effect of 5-BDBD and SB203580 (a p38-MAPK inhibitors) on the release and synthesis of BDNF in BV2 microglia cells treated with 50 μM adenosine triphosphate (ATP).ResultsChronic intermittent administration of NTG resulted in chronic mechanical and thermal hyperalgesia, accompanied by the upregulation of P2X4Rs and BDNF expression. 5-BDBD or ANA-12 prevented hyperalgesia induced by NTG, which was associated with a significant inhibition of the NTG-induced increase in phosphorylated extracellular regulated protein kinases (p-ERK) and calcitonin gene related peptide (CGRP) release in the TNC. Repeated administration of IVM produced sustained hyperalgesia and significantly increased the levels of p-ERK and CGRP release in the TNC. Activating P2X4Rs with ATP triggered BDNF release and increased BDNF synthesis in BV2 microglia, and these results were then reduced by 5-BDBD or SB203580.ConclusionsOur results indicated that the P2X4R contributes to the central sensitization of CM by releasing BDNF and promoting TNC neuronal hyper-excitability. Blocking microglia P2X4R-BDNF signalling may have an effect on the prevention of migraine chronification.
Highlights
Migraine is a complex and severe neurological disorder characterized by repeated attacks
Double immunofluorescence staining showed that P2X4 receptors (P2X4Rs) were mainly double-labelled with Iba1 (Fig. 2d, e), indicating that the P2X4Rs were expressed in microglia, as shown in previous research [6]
P-p38-Mitogen-activated protein kinases (MAPKs) and brain-derived neurotrophic factor (BDNF) increase following recurrent NTG injection, and this is reversed by a P2X4R inhibitor We investigated whether the expression of p38-MAPK, pp38-MAPK and BDNF changed in the trigeminal nucleus caudalis (TNC) following NTG injections
Summary
Migraine is a complex and severe neurological disorder characterized by repeated attacks. Chronic migraine typically progresses from episodic migraine, the mechanisms underlying this progression are not understood. Emerging evidence supports that central sensitization is related to the pathophysiological mechanism of chronic migraine [3]. Central sensitization refers to a condition where central neurons in the trigeminal nociceptive pathway, principally the trigeminal nucleus caudalis (TNC), exhibit increased excitability. Recent evidence suggests that microglia surrounding TNC neurons directly or indirectly influence the establishment of central sensitization. The molecular mechanism that underlies the crosstalk between microglia and neurons of the TNC needs further study. According to our previous study, microglia P2X4 receptors (P2X4Rs) play a pivotal role in the central sensitization of chronic migraine (CM). The molecular mechanism that underlies the crosstalk between microglia P2X4Rs and neurons of the trigeminal nucleus caudalis (TNC) is not fully understood. The aim of this study is to examine the exact P2X4Rs signalling pathway in the development of central sensitization in a CM animal model
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