Role of TNF-α in the Pathogenesis of Migraine

Sudershan, Amrit; Sudershan, Srishty; Sharma, Isha; Kumar, Hardeep; Panjaliya, Rakesh K.; Kumar, Parvinder

doi:10.1155/2024/1377143

Cited by 2 publications

(1 citation statement)

References 106 publications

(105 reference statements)

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“…Among the bioactive molecules released by degranulated mast cells, TNF-a is attracting attention because of its pro-inflammatory capacity and the beneficial effects of TNF-a pathway antagonists on inflammation-related diseases [ 60 , 61 ]. In contrast to the evidence implicating TNF-a in the pathogenesis of migraine [ 62 – 65 ] and our findings here, many people have received anti-TNFα treatment, and no change in migraine symptoms has been reported in these patients. This discrepancy may be due to the complexity of the cause of migraine in humans.…”

Section: Discussioncontrasting

confidence: 99%

PACAP38/mast-cell-specific receptor axis mediates repetitive stress-induced headache in mice

Son,

Zhang,

Shannonhouse

et al. 2024

J Headache Pain

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Background Pain, an evolutionarily conserved warning system, lets us recognize threats and motivates us to adapt to those threats. Headache pain from migraine affects approximately 15% of the global population. However, the identity of any putative threat that migraine or headache warns us to avoid is unknown because migraine pathogenesis is poorly understood. Here, we show that a stress-induced increase in pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), known as an initiator of allosteric load inducing unbalanced homeostasis, causes headache-like behaviour in male mice via mas-related G protein-coupled receptor B2 (MrgprB2) in mast cells. Methods The repetitive stress model and dural injection of PACAP38 were performed to induce headache behaviours. We assessed headache behaviours using the facial von Frey test and the grimace scale in wild-type and MrgprB2-deficient mice. We further examined the activities of trigeminal ganglion neurons using in vivo Pirt-GCaMP Ca2+ imaging of intact trigeminal ganglion (TG). Results Repetitive stress and dural injection of PACAP38 induced MrgprB2-dependent headache behaviours. Blood levels of PACAP38 were increased after repetitive stress. PACAP38/MrgprB2-induced mast cell degranulation sensitizes the trigeminovascular system in dura mater. Moreover, using in vivo intact TG Pirt-GCaMP Ca2+ imaging, we show that stress or/and elevation of PACAP38 sensitized the TG neurons via MrgprB2. MrgprB2-deficient mice showed no sensitization of TG neurons or mast cell activation. We found that repetitive stress and dural injection of PACAP38 induced headache behaviour through TNF-a and TRPV1 pathways. Conclusions Our findings highlight the PACAP38-MrgprB2 pathway as a new target for the treatment of stress-related migraine headache. Furthermore, our results pertaining to stress interoception via the MrgprB2/PACAP38 axis suggests that migraine headache warns us of stress-induced homeostatic imbalance.

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Section: Discussioncontrasting

confidence: 99%

PACAP38/mast-cell-specific receptor axis mediates repetitive stress-induced headache in mice

Son,

Zhang,

Shannonhouse

et al. 2024

J Headache Pain

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The role of kynurenines in migraine-related neuroimmune pathways

Körtési,

Nagy-Grócz,

Vécsei

2024

J Headache Pain

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Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates.

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Role of TNF-α in the Pathogenesis of Migraine

Cited by 2 publications

References 106 publications

PACAP38/mast-cell-specific receptor axis mediates repetitive stress-induced headache in mice

PACAP38/mast-cell-specific receptor axis mediates repetitive stress-induced headache in mice

The role of kynurenines in migraine-related neuroimmune pathways

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