Mast Cell Degranulation Mediates Compound 48/80-İnduced Meningeal Vasodilatation Underlying Migraine Pain

Abstract

Objective: The cranial dura mater contains plenty of mast cells and is principally supplied by the middle meningeal artery which has a key role in the generation of headaches. Neurogenic inflammation caused by perivascular nerve activation and dural vasodilation is held responsible for migraine pain. Dural mast cells contribute neurogenic inflammation and migraine via vasoactive and proinflammatory mediators in their secretory granules. In the present study, it was aimed to investigate vasoactive effect of mast cell degranulating agent compound 48/80 induced dural mast cell degranulation on the middle meningeal artery and its anterior and posterior branches. Methods: Isolated skulls obtained from male Wistar rats were divided into 2 halves. The skull cavities with intact the dura mater were applied synthetic interstitial fluid for control group or mast cell degranulating agent compound 48/80 (10 µg/ml) in synthetic interstitial fluid for treated group at 37 o C for 15 min. Diameters of middle meningeal artery and its anterior and posterior branches were measured and mast cells were counted from whole-mount preparations of meningeal dura mater. Results: While compound 48/80 induced massive degranulation of dural mast cells (P<0.01), it did not change the number of mast cells in the dura mater. Moreover, compound 48/80 increased diameter of middle meningeal artery (P<0.01) and its anterior (P<0.05) and posterior (P<0.01) branches, respectively compared to synthetic interstitial fluid treatment. Conclusion: Dural mast cell degranulation causes dilatation of middle meningeal artery which is involved in the pathophysiology of migraine, therefore testing of mast cell stabilizing agents in vivo models of migraine pain may promise hope for the next big things in the treatment of migraine headaches.

Mast cell activation ameliorates pentylenetetrazole‐induced seizures in rats: The potential role for serotonin

“…Although neuroinflammation is a protective response of the innate immunity in the CNS intended to eliminate detrimental stimuli and initiate the recovery process, persistent neuroinflammation can lead to destructive phenomena such as neuronal hyperexcitability and neuronal death (Hendriksen et al., 2017; Lyman et al., 2014). Microglia and MCs are central innate immune cells in the CNS (Kilinc et al., 2019; Kilinc, Dagistan, & Tore, 2018; Xanthos & Sandkühler, 2014). Cytokines such as IL‐1 β, IL‐6, and tumor necrosis factor‐α (TNF‐α) released from immune cells in response to detrimental stimuli are reported to be capable of increasing blood–brain barrier permeability, thus resulting in neuroinflammation (Hendriksen et al., 2017; Koyuncu Irmak et al., 2019; Taskiran, Ergul, et al., 2020; Taskıran, Ozdemir, et al., 2020).…”

“…The mediator release patterns of MCs depend on the types of stimuli and microenvironmental circumstances, and they are therefore capable of either aggravating or alleviating inflammatory processes (Nelissen et al., 2013). The number and degree of activation of MCs in the meninges and brain involved in both health and neuroimmune disorders both fluctuate in line with stress and various endogenous and exogenous triggers (Kilinc, Ankarali, et al., 2020; Kilinc, Dagistan, et al., 2017; Kilinc, Dagistan, & Tore, 2018; Olivera et al., 2018; Theoharides, 2020). It was once thought that activation of MCs always promotes inflammatory processes; however, it has recently been revealed that the outcome of MC actions is not always harmful for the host, and may also restrict disease progression (Beghdadi et al., 2011; Olivera et al., 2018).…”

The comparison of effects of applications of compound 48/80 and mast cell mediator suspension on inflammation in rats: A methodological study for acute inflammatory pain

“…Chemical or mechanical irritation of the dura mater causes release of vasoactive and proinflammatory neuropeptides such as SP and CGRP from trigeminal nerve terminals innervating the dura mater (4,30,31). Released SP and CGRP leads to plasma protein extravasation, vasodilatation of meningeal blood vessels and dural mast cell degranulation which constitute triple trivet of dural neurogenic inflammation underlying migraine pain (5). Moreover degranulated mast cells in the dura mater release vasoactive, nociceptive and proinflammatory mediators such as SP, CGRP, serotonin, prostaglandins, histamine and a plethora of cytokines (2) which, in turn, further strengthen dural neurogenic inflammation and pain.…”

“…MCs participate in the inflammatory processes by releasing various pronociceptive, vasoactive and pro-inflammatory mediators from their granules through a process called degranulation (4). MCderived mediators such as serotonin, prostaglandin, histamine, tryptase, tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-1β are able to trigger and enhance inflammatory reactions (5). Increments in the number and degranulation of MCs Animal models of inflammatory pain are important tools to investigate pain mechanisms and analgesic effects of potential drugs for the treatment of inflammatory diseases.…”