Abstract
BackgroundMigraine is a debilitating neurological disorder involving abnormal trigeminovascular activation and sensitization. However, the underlying cellular and molecular mechanisms remain unclear.MethodsA rat model of conscious migraine was established through the electrical stimulation (ES) of the dural mater surrounding the superior sagittal sinus. Using patch clamp recording, immunofluorescent labelling, enzyme-linked immunosorbent assays and western blot analysis, we studied the effects of ES on sensory neuronal excitability and elucidated the underlying mechanisms mediated by voltage-gated ion channels.ResultsThe calcitonin gene-related peptide (CGRP) level in the jugular vein blood and the number of CGRP-positive neurons in the trigeminal ganglia (TGs) were significantly increased in rats with ES-induced migraine. The application of ES increased actional potential firing in both small-sized IB4-negative (IB4−) and IB4+ TG neurons. No significant changes in voltage-gated Na+ currents were observed in the ES-treated groups. ES robustly suppressed the transient outward K+ current (IA) in both types of TG neurons, while the delayed rectifier K+ current remained unchanged. Immunoblot analysis revealed that the protein expression of Kv4.3 was significantly decreased in the ES-treated groups, while Kv1.4 remained unaffected. Interestingly, ES increased the P/Q-type and T-type Ca2+ currents in small-sized IB4− TG neurons, while there were no significant changes in the IB4+ subpopulation of neurons.ConclusionThese results suggest that ES decreases the IA in small-sized TG neurons and increases P/Q- and T-type Ca2+ currents in the IB4− subpopulation of TG neurons, which might contribute to neuronal hyperexcitability in a rat model of ES-induced migraine.
Highlights
Migraine is a debilitating neurological disorder involving abnormal trigeminovascular activation and sensitization
Decreased mechanical thresholds and increased calcitonin gene-related peptide (CGRP) in a rat model of migraine Many animal models of migraine have been constructed through the electrical stimulation (ES) of trigeminal nerveinnervating tissues, such as the trigeminal ganglion (TG) [34], the dural arteries, the dura mater and the superior sagittal sinus [35]
We examined whether the level of CGRP is increased in the rat model of ES-induced migraine and found that the application of ES significantly increased the levels of CGRP in the jugular vein blood by ~ 3-fold
Summary
Migraine is a debilitating neurological disorder involving abnormal trigeminovascular activation and sensitization. There is great diversity of channel subtypes due to the multiple genes that encode channel α1 subunits, the coassembly of a variety of ancillary channel subunits, and alternative splicing [9] This allows these channels to fulfil highly specialized roles in specific neuronal subtypes and at particular subcellular loci [9, 10]. Neuronal disorders, e.g., epilepsy, episodic ataxia, familial hemiplegic migraine, and Parkinson’s disease, may result from the dysfunction of voltage-gated Na+ (Nav), K+ (Kv) and Ca2+ (Cav) channels [12]. Voltage-gated ion channel subunits have been identified on dural afferents, and these subunits underlie trigeminal nociceptor activation and cutaneous allodynia in migraine [14, 15]. The alteration of these channels in the pathogenesis of migraine has not been fully validated in rat animal models of migraine
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