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Papers of the Week

Papers: 10 Dec 2022 - 16 Dec 2022

Animal Studies


2022 Dec 09

Eur J Neurosci

Meningeal mast cell-mediated mechanisms of cholinergic system modulation in neurogenic inflammation underlying the pathophysiology of migraine.


Growing evidence indicates that the parasympathetic system is implicated in migraine headache. However, the cholinergic mechanisms in the pathophysiology of migraine remain unclear. We investigated the effects and mechanisms of cholinergic modulation and a mast cell stabilizer cromolyn in the nitroglycerin-induced in-vivo migraine model and in-vitro hemiskull preparations in rats. Effects of cholinergic agents (acetylcholinesterase inhibitor neostigmine, or acetylcholine, and muscarinic antagonist atropine) and mast cell stabilizer cromolyn or their combinations were tested in the in-vivo and in-vitro experiments. The mechanical hyperalgesia was assessed by von-Frey hairs. Calcitonin gene-related peptide (CGRP) and C-fos levels were measured by enzyme-linked immunosorbent assay. Degranulation and count of meningeal mast cells were determined by toluidine-blue staining. Neostigmine augmented the nitroglycerin-induced mechanical hyperalgesia, trigeminal ganglion CGRP levels, brainstem CGRP and C-fos levels, as well as degranulation of mast cells in-vivo. Atropine inhibited neostigmine-induced additional increases in CGRP levels in trigeminal ganglion and brainstem while it failed to do this in the mechanical hyperalgesia, C-fos levels, and the mast cell degranulation. However, all systemic effects of neostigmine were abolished by cromolyn. The cholinergic agents or cromolyn did not alter basal release of CGRP, in-vitro, but cromolyn alleviated the CGRP-inducing effect of capsaicin while atropine failed to do it. These results ensure for a first time direct evidence that endogenous acetylcholine contributes to migraine pathology mainly by activating meningeal mast cells while muscarinic receptors are involved in CGRP release from trigeminal ganglion and brainstem, without excluding the possible role of nicotinic cholinergic receptors.