CGRP outflow into jugular blood and cerebrospinal fluid and permeance for CGRP of rat dura mater

Miriam Risch,Karl Messlinger,Mária Dux,Birgit Vogler

doi:10.1186/s10194-021-01320-9

Miriam Risch, Karl Messlinger + Show 2 more

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https://doi.org/10.1186/s10194-021-01320-9

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Abstract

BackgroundCalcitonin gene-related peptide (CGRP) is released from activated meningeal afferent fibres in the cranial dura mater, which likely accompanies severe headache attacks. Increased CGRP levels have been observed in different extracellular fluid compartments during primary headaches such as migraine but it is not entirely clear how CGRP is drained from the meninges.MethodsWe have used an in vivo preparation of the rat to examine after which time and at which concentration CGRP applied onto the exposed parietal dura mater appears in the jugular venous blood and the cerebrospinal fluid (CSF) collected from the cisterna magna. Recordings of meningeal (dural) and cortical (pial) blood flow were used to monitor the vasodilatory effect of CGRP. In a new ex vivo preparation we examined how much of a defined CGRP concentration applied to the arachnoidal side penetrates the dura. CGRP concentrations were determined with an approved enzyme immunoassay.ResultsCGRP levels in the jugular plasma in vivo were slightly elevated compared to baseline values 5-20 min after dural application of CGRP (10 μM), in the CSF a significant three-fold increase was seen after 35 min. Meningeal but not cortical blood flow showed significant increases. The spontaneous CGRP release from the dura mater ex vivo was above the applied low concentration of 1 pM. CGRP at 1 nM did only partly penetrate the dura.ConclusionsWe conclude that only a small fraction of CGRP applied onto the dura mater reaches the jugular blood and, in a delayed manner, also the CSF. The dura mater may constitute a barrier for CGRP and limits diffusion into the CSF of the subarachnoidal space, where the CGRP concentration is too low to cause vasodilatation.

Highlights

Calcitonin gene-related peptide (CGRP) is released from activated meningeal afferent fibres in the cranial dura mater, which likely accompanies severe headache attacks
CGRP from afferents innervating pial blood vessels supplying the superficial cortex and the medulla oblongata is probably directly released into the cerebrospinal fluid (CSF), because these vessels are equipped with a blood-brain barrier (BBB) [31, 34]
Five minutes after topical application of vehicle (SIF) onto the dura mater the CGRP level reached its lowest value with 57.9 ± 8.8 pg/mL before it continuously increased after CGRP at 10 μM was applied onto the dura

Summary

Introduction

Calcitonin gene-related peptide (CGRP) is released from activated meningeal afferent fibres in the cranial dura mater, which likely accompanies severe headache attacks. During massive activation of trigeminal afferents, CGRP is thought to be released from peripheral fibres of trigeminal afferents innervating meninges (dura mater and pia mater, large intracerebral arteries) and extracranial tissues, from the central terminals of these fibres in the spinal trigeminal nucleus and possibly from the neuronal somata within the trigeminal ganglion [11, 27–30]. CGRP released from trigeminal fibres outside the blood brain barrier are probably drained via intra- and extracranial venous vessels into the jugular blood [31]. CGRP released from afferents innervating cerebral blood vessels and from activated central terminals of primary afferents within the spinal trigeminal nucleus may diffuse into the CSF or is transported by lymphatic vessels into the venous system [35–37]. CGRP can be secreted together with CSF through the Pacchioni granulations into the blood of the superior sagittal sinus [38–40]

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