Alteration Of Pituitary Adenylate Cyclase Activating Polypeptide And Related Receptors In Migraine

Migraine is one of the most neurological common diseases,and the pathogenic mechanism of migraine is not fully clear.Preclinical experimental studies have revealed that pituitary adenylate cyclase-activating polypeptide(PACAP)has a crucial role in activation of trigeminovascular system and human studies have shown that exogenous PACAP could induce migraine-like headache in migraine patients but not in healthy volunteers,suggesting the possible role for PACAP in the pathogenesis of migraine.However,the endogenous alterations of PACAP and related receptors in the process of repeated migraine attacks are still unclear,and whether the levels of endogenous PACAP could be used to distinguish between migraine and tension-type headache(TTH)remains unknown.Thus,the aim of this study was to compare interictal plasma PACAP levels between migraineurs and patients with TTH,and to investigate the peripheral and central alterations of endogenous PACAP and related receptors in two migraine rodent models after repetitive electrical and chemical dural stimulations.In the clinical research part of this project,interictal plasma levels of PACAP were measured in 133 migraineurs,106 patients with TTH,and 50 controls using enzyme-linked immunoassays.We further evaluated the relationships between interictal PACAP plasma concentrations and clinical parameters.In the basic research part,two rodent models of migraine were established by repeated chemical and electrical dural stimulation.The expression of PACAP was quantified in plasma,trigeminal ganglia(TG)and brainstem by means of radioimmunoassay.Western-blot analysis and real time RT-PCR were used to measure the protein and mRNA expression of PACAP related receptors(PAC1 ?VPAC1 and VPAC2)in the TG and brainstem to identify changes associated with repetitive application of electrical stimulation or chemical stimulation to the dura mater surrounding the superior sagittal sinus.In the present study,we found that migraineurs had significantly lower interictal plasma PACAP levels than patients with TTH and healthy controls.Plasma PACAP levels were significantly lower in patients with episodic migraine(EM)than in patients with episodic tension-type headache(ETTH)and also in patients with chronic migraine(CM)than in patients with chronic tension-type headache(CTTH).Interictal PACAP levels were negatively correlated with duration in the CM group.In the basic researchpart,we found that PACAP level was significantly increased in plasma and TG,and the expression of PAC1 and VPAC1 receptors were increased in both TG and brainstem,while the VPAC2 receptor was increased only in TG after repetitive acute electrical dural stimulations.While after repetitive chronic chemical dural stimulations,significant decrease of PACAP levels and increase of PAC1 receptor expression were observed in TG,however,there was no significant different of the VPAC1 and VPAC2 receptors expression.In conclusion,the present findings demonstrated the different changes in interictal plasma PACAP levels in migraine and TTH,and the lower PACAP levels in migraineurs could further contribute to the growing list of differences between migraine and TTH.This research also showed there was excessive release of PACAP during acute period and PACAP exhaustion after repetitive chronic stimulations accordingly,as well as the up-regulation of PACAP related receptors in the process of repetitive dural stimulations,suggesting PACAP is involved in the pathogenesis of migraine and its related receptors might be the new therapeutic target for migraine.