| BackgroundMigraine is a common and disabling neurovascular disease with character of repeated attack of severe headaches, which affects approximately15％of the population. This disorder has made a severe impact on both quality of life in patients and society. The activation of trigeminovascular system triggers the neurogenic inflammation of cranial blood vessels and the generation of headache. Vasodilation of the meningeal vessels is due in part to CGRP release, plasma extravasation, and mast cell degranulation contribute to the release of proinflammatory substances into the meninges, which can activate meningeal primary afferents ultimately resulting in migraine pain.Accumulating data indicate that activation of peripheral trigeminal nociceptors in the intracranial blood vessels, such as the MMA and the meninges, results in the release of bioactive mediators, including neuropeptides or neurotrophins, such as neurokinin A, substance P, calcitonin gene related peptide (CGRP), glial cell line-derived neurotrophic factor GDNF, neurturin, persephin, Artn, and etc., which is often related to the generation and modulation of pain. Of these mediators, Artemin (Artn), a member of the glial cell-derived neurotrophic factor family, which signals through the receptor complex of its specific GDNF family receptor (GFR)a3and Ret. Artn expresses in vascular smooth muscle cells and modulates the development and the function of the nervous system and regulates the innervation of sympathetic postganglionic neurons (SPGNs) in the vasculature. Many foreign scholars studies suggested that the expression of Artn was increased at peripheral inflamed tissues and the injection of Artn exhibited hyperalgesia in Sensitive oganizations. GFRa3receptor is expressed in a subset of primary afferent neurons that appear to function as nociceptor and contribute to inflammatory hyperalgesia. In addition, the detection of the distribution of Artn and its receptor-GFRa3in the dura mater of rats suggests that Artn contributes to migraine pain indirectly via the SPGN as well as directly by the sensitization and/or activation of dural afferents. Artn potentiates TRPV1signaling in DRG neurons and trigeminal sensory neurons that appears to contribute to thermal hyperalgesia associated with inflammation tissues. Moreover, activation of TRPV1, a calcium permeable ion channel, has been shown to promote the release of CGRP from a number of tissues. These findings suggest that Artn may play an important role in the pathogenesis of migraine.ObjectivesRecently, we found that the ligation of middle meningeal artery and superficial temporal artery and severance of greater superficial petrosal nerve was effective for the treatment of intractable cases of migraine, suggesting the involvement of middle meningeal artery in migraine pathophysiology. In this work, we established a rat migraine model by administration of nitroglycerin (NTG) and heat coagulation of the middle meningeal artery (MMA) to observe the expression of Artn in migraine rat dura mater induced by nitroglycerin and investigate the mechanism of Artn in the pathogenesis of migraine and explore the efficacy mechanism of heating coagulation of middle meningeal artery in the treatment of intractable cases of migraine. According this we can provide a theoretical and experimental basis for evaluating the surgery for the treatment of intractable cases of migraine.MethodsSeventy-eight female Wistar rats,250-300g, were randomly divided into four groups. In group A, rats were treated with isotonic saline that were served as absolute control and sacrificed at different time points of1,2,3,4or6h after the saline injection to obtain the tissue samples; in group B, rats were injected with nitroglycerin (NTG,10mg/kg) to set up the migraine model and the migrainous rats were sacrificed at1,2,3,4or6h after injection of NTG; in group C, rats were firstly subjected to heat coagulation of MMA and, subsequently, injected with NTG (10mg/kg) after a survival period of three days; and in group D, rats were merely exposed the MMA and then injected with NTG (10mg/kg). The tissue samples were collected6h post-injection of NTG in group C and D. Following the injection, the animal’s behaviors were continuously recorded for three hours by an observer. Using this model, we investigated the expression of Artn in the dura mater by means of double immunofluorescence labeling, RT-PCR, western blot, and immunohistochemistry.ResultsThe rats in group A occasionally presented scratching head, but, rats in B and D appeared a series of symptoms, such as frequent scratching head, climbing cage, grooming, and other phenomena of irritability. Remarkably, rats in group C presented minor scratching and slightly irritable symptoms compared with those in group B and D. The positive expression of Artn in rats were detected at all time points in the control groups, but there were no significant differences at all time points (p>0.05). Compared with injection of NS, the expression of the mRNA of Artn at2h after injection NTG rapidly up-regulated, hereafter, the expression of the mRNA of Artn lowered and tended to the level of the control group at6h after NTG-treated. The expression of Artn protein increased at3h after NTG injection and continuously up-regulated to6h. The Artn expressions in the dura of rats after NTG injection from3h to6h were increased than that in corresponding isotonic saline rats (P＜0.05). Artn protein expressions were no statistical difference in isotonic saline groups. As the peak of Artn protein expression appeared at6h after NTG injection, we chose this time point for our next experiments in both operation and sham operation groups. The Artn expressions in three interventional groups were increased than that in control group (P<0.05). Further, the Artn protein expression in group C was visibly reduced compared with that in group B or D (P<0.05). However, there was no statistical difference between group B and D (P>0.05).ConclusionsArtn play a role in the pathogenesis of migraine via its up-regulated expression, which is likely to activate TRPV1and, in turn, to mediate the release of CGRP, thereby serving as a promoter to elicit the migraine pain. |
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