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<em>Ex Vivo</em> Release of Calcitonin Gene-Related Peptide from the Trigeminovascular System in Rodents

Calcitonin gene-related peptide (CGRP) was first discovered in the 1980s as a splice variant from the calcitonin gene. Since its discovery, its role in ...

Rigshospitalet, University of Copenhagen

To investigate if PACAP and VIP have an effect on CGRP release or NOS activity in the trigeminal ganglion and trigeminal nucleus caudalis and if there can be a difference in effect between PACAP and VIP on these two systems. Furthermore, we investigate if PACAP co-localize with CGRP and/or nNOS in the two tissues.

PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor.

In healthy human volunteers and in migraineurs, pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) infusion caused sustained vasodilation of the middle meningeal artery (MMA) and an immediate as well as a delayed headache. All the study subjects experienced facial flushing. Mast cells (MCs) might have a role in the long-lasting effect of PACAP-38 infusion. We hypothesized that in mast cell-depleted (MCD) rats the vascular responses to PACAP-38 would be lesser than in control rats because of a lack of vasodilatory products released during MC degranulation.

PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat: possible involvement of mast cells.

Migraine patients develop attacks several hours after intravenous infusion of glyceryl trinitrate. Due to the short half-life of nitric oxide, this delayed migraine cannot be caused by a direct action of nitric oxide derived from glyceryl trinitrate. The involvement of meningeal inflammation and dural mast cell degranulation is supported by the effectiveness of prednisolone on glyceryl trinitrate-induced delayed headache.

Mechanisms of glyceryl trinitrate provoked mast cell degranulation.

Glyceryl trinitrate induces headache during infusion to man and migraine patients develop an additional migraine attack a few hours after the infusion. Recently, we have moved this model into rat with the intention of developing an animal model predictive of migraine therapy. In the current paper we have studied the effect of glyceryl trinitrate infusion on three different rat behaviors.

Infusion of low dose glyceryl trinitrate has no consistent effect on burrowing behavior, running wheel activity and light sensitivity in female rats.

Prostaglandins (PGs), particularly prostaglandin D (PGD), E (PGE), and I (PGI), are considered to play a role in migraine pain. In humans, infusion of PGD causes lesser headache as compared to infusion of PGE and PGI. Follow-up studies in rats have shown that infusion of PGE and PGI dilate the middle meningeal artery (MMA), and mRNA for PGE and PGI receptors is present in rat trigeminovascular system (TVS) and in the brain structures associated with pain. In the present study, we have characterized the dilatory effect of PGD on rat MMA and studied the relative mRNA expression of PGD receptors and lipocalin-type of PGD synthase (L-PGDS).

Effect of PGD on middle meningeal artery and mRNA expression profile of L-PGD synthase and DP receptors in trigeminovascular system and other pain processing structures in rat brain.

In migraineurs pituitary adenylate cyclase activating peptide1-38 (PACAP1-38) is a potent migraine provoking substance and the accompanying long lasting flushing suggests degranulation of mast cells. Infusion of the closely related vasoactive intestinal peptide (VIP) either induces headache or flushing. This implicates the pituitary adenylate cyclase activating peptide type I receptor (PAC1) to be involved in the pathophysiology of PACAP1-38 provoked headaches. Here we review studies characterizing the effects of mainly PACAP but also of VIP on cerebral and meningeal arteries and mast cells.

PACAP and its receptors in cranial arteries and mast cells.

Transient receptor potential ankyrin 1 (TRPA1) channels may have a role in migraine as some substances known to cause headache activate the channel. In the craniovascular system such activation causes a calcitonin gene-related peptide (CGRP)-dependent increase in meningeal blood flow. TRPA1 channels in the endothelium of cerebral arteries cause vasodilation when activated. The headache preventive substance feverfew inhibits activation of TRPA1 channels. In this study we aim to compare and characterize the effect of the TRPA1 agonist allyl isothiocyanate (AITC) on the diameter of rat dural and pial arteries in vivo.

Article	Year
PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides\| PubMed ID: 24508136	2014
PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat: possible involvement of mast cells. Cephalalgia : an international journal of headache\| PubMed ID: 24563332	2014
Mechanisms of glyceryl trinitrate provoked mast cell degranulation. Cephalalgia : an international journal of headache\| PubMed ID: 25724914	2015
Infusion of low dose glyceryl trinitrate has no consistent effect on burrowing behavior, running wheel activity and light sensitivity in female rats. Journal of pharmacological and toxicological methods\| PubMed ID: 27066766	2016
Effect of PGD on middle meningeal artery and mRNA expression profile of L-PGD synthase and DP receptors in trigeminovascular system and other pain processing structures in rat brain. Pharmacological reports : PR\| PubMed ID: 27898338	2017
PACAP and its receptors in cranial arteries and mast cells. The journal of headache and pain\| PubMed ID: 29460121	2018
Effect of TRPA1 activator allyl isothiocyanate (AITC) on rat dural and pial arteries. Pharmacological reports : PR\| PubMed ID: 31132686	2019

Inger Jansen-Olesen

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