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Citation: Spekker, E.; Tanaka, M.;
Szabó, Á.; Vécsei, L. Neurogenic
Inflammation: The Participant in
Migraine and Recent Advancements in
Translational Research. Biomedicines
2022,10, 76. https://doi.org/
10.3390/biomedicines10010076
Academic Editor: Marco Segatto
Received: 2 November 2021
Accepted: 27 December 2021
Published: 30 December 2021
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biomedicines
Review
Neurogenic Inflammation: The Participant in Migraine and
Recent Advancements in Translational Research
Eleonóra Spekker 1, Masaru Tanaka 1,2 ,Ágnes Szabó2and LászlóVécsei 1,2, *
1Neuroscience Research Group, Hungarian Academy of Sciences, University of Szeged (MTA-SZTE),
H-6725 Szeged, Hungary; spekker.eleonora@med.u-szeged.hu (E.S.);
tanaka.masaru.1@med.u-szeged.hu (M.T.)
2Interdisciplinary Excellence Centre, Department of Neurology, Albert Szent-Györgyi Medical School,
University of Szeged, H-6725 Szeged, Hungary; szabo.agnes.4@med.u-szeged.hu
*Correspondence: vecsei.laszlo@med.u-szeged.hu; Tel.: +36-62-545-351; Fax: +36-62-545-597
Abstract:
Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing
headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits
various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical
activity consistently contributes to worsening pain. Despite the intensive research, little is still known
about the pathomechanism of migraine. It is widely accepted that migraine involves activation and
sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neu-
ropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including
vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranu-
lation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is
assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura
mater triggers activation and sensitization of the trigeminal system and causes numerous molecular
and behavioral changes; therefore, this is a relevant animal model of acute migraine. This narrative
review discusses the emerging evidence supporting the involvement of neurogenic inflammation and
neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical
research and the novel therapeutic approaches to the disease.
Keywords:
primary headache; migraine; trigeminal system; neuropeptides; neurogenic inflammation;
animal model; inflammatory soup; dura mater; immune system; migraine treatment
1. Introduction
Migraine is a common neurological condition as the third most prevalent disease
worldwide [
1
]. According to the Global Burden of Disease Study 2016, migraine is the
second leading cause of disability [
2
]. The prevalence of migraine is 14.7%, and it is three
times more common in women than men; in addition, women are less responsive to treat-
ment [
3
]. Moreover, as migraine is a chronic episodic disorder that predominantly affects
the working sector of a population, it thus has high social costs [
4
]. Migraine is ascribed to
complicated, multifactorial conditions that give rise to substantial variations among pa-
tients and single patient responses to treatments [
5
]. Clinically, migraine can cause a variety
of symptoms besides recurrent headaches, such as allodynia, photo- and phonophobia, and
decreased daily activity, which can last from 4 to 72 h without treatment [
6
]. Due to its own
pathogenesis and the fact that no other cause can be associated with the development of
the disease, migraine belongs to the family of primary headache disorders [7].
The clinical course of migraine can be divided into different stages: the prodrome
phase, a possible aura, followed by the headache, and the recovery stage (postdrome). The
prodrome phase typically occurs up to a few days before the headache attack, and changes
in well-being and behavior are experienced, while fatigue and impaired concentration
occur as frequent complaints [
8
]. In 25% of the migraineurs, a temporary dysfunction of
Biomedicines 2022,10, 76. https://doi.org/10.3390/biomedicines10010076 https://www.mdpi.com/journal/biomedicines
Biomedicines 2022,10, 76 2 of 25
the central nervous system (CNS), the aura phenomenon, occurs [
9
]. The most common
symptoms are visual (e.g., visual field disturbances), but sensory or speech disturbances
and rarely motor symptoms can also be observed [
6
,
10
–
12
]. The typical aura appears before
or at the beginning of the headache and lasts up to one hour. The headache in migraineurs
is moderate or strong and throbbing, lasting 4–72 h, and is associated with sensitivity to
light/sound and nausea/vomiting. Physical activity worsens the symptoms, and thus, the
migraineurs seek rest (Figure 1A).
Biomedicines 2022, 10, x FOR PEER REVIEW 2 of 27
changes in well-being and behavior are experienced, while fatigue and impaired concen-
tration occur as frequent complaints [8]. In 25% of the migraineurs, a temporary dysfunc-
tion of the central nervous system (CNS), the aura phenomenon, occurs [9]. The most com-
mon symptoms are visual (e.g., visual field disturbances), but sensory or speech disturb-
ances and rarely motor symptoms can also be observed [6,10–12]. The typical aura appears
before or at the beginning of the headache and lasts up to one hour. The headache in mi-
graineurs is moderate or strong and throbbing, lasting 4–72 h, and is associated with sen-
sitivity to light/sound and nausea/vomiting. Physical activity worsens the symptoms, and
thus, the migraineurs seek rest (Figure 1A).
Figure 1. The stages and the pathways of migraine. (A) The stages of migraine attack: the pro-
drome phase, a possible aura, followed by the headache, and subsequently the postdrome. A
strong headache is frequently accompanied with nausea, vomiting, and sensitivity to light, which
lasts 4 to 72 h. (B) Mechanisms and structures involved in the pathogenesis of migraine: CTX, cor-
tex; NO, nitric-oxide; CSD, cortical spreading depression; Th, thalamus; hTh, hypothalamus; LP,
lateral posterior nucleus; VPM, ventral posteromedial nucleus; VPL, ventral posterolateral nu-
cleus; PAG, periaqueductal grey matter; LC, locus coeruleus; TCC, trigeminocervical complex;
SSN, superior salivatory nucleus; SpV, spinal trigeminal nucleus caudalis; TG, trigeminal gan-
glion; SPG, sphenopalatine ganglion; V1, ophthalmic nerve; V2, maxillary nerve; V3, mandibular
nerve; CGRP, calcitonin gene-related peptide; SP, substance P; PACAP, pituitary adenylate
Figure 1.
The stages and the pathways of migraine. (
A
) The stages of migraine attack: the pro-
drome phase, a possible aura, followed by the headache, and subsequently the postdrome. A strong
headache is frequently accompanied with nausea, vomiting, and sensitivity to light, which lasts
4 to 72 h. (
B
) Mechanisms and structures involved in the pathogenesis of migraine: CTX, cortex;
NO, nitric-oxide; CSD, cortical spreading depression; Th, thalamus; hTh, hypothalamus; LP, lateral
posterior nucleus; VPM, ventral posteromedial nucleus; VPL, ventral posterolateral nucleus; PAG,
periaqueductal grey matter; LC, locus coeruleus; TCC, trigeminocervical complex; SSN, superior sali-
vatory nucleus; SpV, spinal trigeminal nucleus caudalis; TG, trigeminal ganglion; SPG, sphenopalatine
ganglion; V1, ophthalmic nerve; V2, maxillary nerve; V3, mandibular nerve; CGRP, calcitonin gene-
related peptide; SP, substance P; PACAP, pituitary adenylate cyclase-activating polypeptide; NKA,
neurokinin A; PPE, plasma protein extravasation; TNF
α
, tumour necrosis factor alpha; IL, interleukin.
Biomedicines 2022,10, 76 3 of 25
Despite intensive research, the pathomechanism of migraine is still unclear; however,
activation and sensitization of the trigeminal system (TS) is essential during the attacks [
13
].
The TS is responsible for processing painful stimuli from the cortical area; during its
activation, neurotransmitters, such as calcitonin gene-related peptide (CGRP), substance P
(SP), pituitary adenylate cyclase-activating polypeptide (PACAP), and neurokinin A (NKA),
are released both at the peripheral and central arm of the primary sensory neurons [
14
].
The neuropeptide release can induce mast cell degranulation and plasma extravasation,
leading to neurogenic inflammation (NI) [
15
]. In the meantime, activation of the second-
order neurons occurs in the caudal trigeminal nucleus (TNC) and their axons ascend to
terminate in the thalamus, and the nociceptive information is projected to the primary
somatosensory cortex [
16
]. Recent neuroimaging studies revealed other regions of the
CNS (e.g., cerebellum, insula, pulvinar) that might play a role in the modulation of pain
sensation [17,18] (Figure 1B).
In the 1950s, Ray and Wolff developed the first theory about the pathomechanism of
migraine. They believed that migraine pain was caused by extracranial vasodilation, while
intracranial vasospasm was responsible for aura symptoms [
19
]. At that time, this theory
was in line with the pharmacological observations that the potent vasodilator amyl nitrate
aborted the aura phase; meanwhile, ergotamine with vasoconstrictive properties decreased
the headache [
20
]. Since vascular changes do not explain all the symptoms experienced
during migraine attacks, new theories emerged regarding the pathomechanism of migraine.
The most widely accepted theory is focusing on the so-called cortical spreading
depression (CSD) first described by Leao and Morison [
21
], which may be the equivalent
of the aura phenomenon [
22
] playing a role in the development of migraine attacks [
23
].
During CSD, depolarization following an excitatory wave across the cerebral cortex changes
cerebral blood supply, increases tissue metabolism, and releases amino acids and nitric
oxide in the cortex, which activates nerves running in the dura, thus dilating the dural
vessels, leading to sterile inflammation [
24
]. Under experimental conditions, CSD can
activate secondary trigeminal nociceptors [
25
], suggesting that susceptibility to CSD might
be responsible for the appearance of the attack.
Weiller and colleagues observed that the dorsolateral pons and the dorsal midbrain
involving the nuclei nucleus raphe magnus (NRM), nucleus raphe dorsalis (DR), locus
coeruleus (LC), and the periaqueductal grey matter (PAG) are activated during a migraine
attack, which persists even after triptan treatment [
26
]. These nuclei can influence TNC
activity, and they are involved in the transmission of pain. Brainstem serotonergic (NRM
and PAG) and adrenergic (LC) nuclei contribute to the activation of the trigeminovascular
system [
27
]. These brainstem areas, in addition to the trigeminovascular system, have a
bidirectional connection with thalamus and hypothalamus. The thalamus has a role in
integrating nociceptive inputs in migraine and pain sensation. The hypothalamus has
direct connections with many structures involved in pain processing, including the nucleus
tractus solitarius, rostral ventromedial medulla, PAG, and NRM [
28
–
30
]. It is hypothesized
that the altered function of these brainstem migraine generators also plays a major role in
attack development.
Nowadays, the most accepted concept is that migraine is a neurovascular disorder,
which originates in the CNS, causing hypersensitivity to the peripheral trigeminal nerve
fibers that innervate the vessels of the meninges.
This narrative review discusses the processes underlying the pathomechanism of
migraine, focusing on the role of neuropeptides and neurogenic inflammation. Furthermore,
it emphasizes the importance of preclinical translational research, which has led to current
understanding of migraine and summarizes the novel potential therapeutic options for
migraine.
Biomedicines 2022,10, 76 4 of 25
2. Dura Mater in Migraine
The dura mater, its vasculature supply, and the cerebral blood vessels are the only
structures containing nociceptive nerve fibers [
31
]. The role of dura mater in migraine pain
was widely examined. Ray and Wolff found that electrical stimulation of dural and cerebral
vessels can cause nausea and the perception of headache-like pain in humans [
19
]. The dura
mater is the outermost layer of the meninges and is located directly underneath the skull
and vertebral column bones. The three branches of the trigeminal nerve (ophthalmic (V1),
maxillary (V2), and mandibular (V3)) innervate the face and head region [
32
]. Dowgjallo
and Grzybowski were the first to find the origin of meningeal nerve fibers in the trigeminal
ganglion (TG) [
33
,
34
]. The tentorial nerve (a branch of the ophthalmic nerve) innervates
most of the supratentorial dura; this nerve supplies the falx cerebri, calvarial dura, and
superior surface of the tentorium cerebelli, forming a dense plexus with the arteries that
form the vascular intracranial pain-sensitive structures [
35
]. The afferents innervating
intracranial structures are collectively referred to as the trigeminovascular system [
36
,
37
].
Strassmann described that peripheral trigeminovascular neurons become mechanically
hypersensitive to dural stimulation, which explains the pulsation and intensification of
headache in case of cough or bending [
38
]. Furthermore, Burstein et al. observed that
stimulation of the dura causes prolonged sensitization of central trigeminovascular neurons
in the spinal trigeminal nucleus [
39
]. Several studies have shown peptidergic trigeminal
afferents to innervate the dura mater [40–42].
3. Neuropeptides and Neurotransmitters
Meningeal nerve fibers are immunoreactive for CGRP, SP, NKA, neuropeptide Y (NPY),
and vasoactive intestinal peptide (VIP), among others [
43
]. CGRP plays multiple roles
in neurogenic inflammation [
44
]. In pharmacological and immunological experiments,
antagonism of CGRP supported that CGRP is indirectly involved in plasma extravasation,
which is primarily caused by SP and NKA [
45
]. Together with SP, CGRP can trigger mast
cell degranulation to release proinflammatory and inflammatory compounds [
46
]. Beside
these, dural mast cells and satellite glia express the CGRP receptor [
47
]. It is suggested that
satellite glia and neurons are involved in a positive feedback loop of CGRP synthesis and
release, maintaining increased inflammation and sensitization [48].
SP is widely distributed in the central and peripheral nervous systems of verte-
brates [
49
]. In the CNS, it is present in the dorsal root ganglion, spinal cord, hippocampus,
cortex, basal ganglia, hypothalamus, amygdala, and TNC [
50
,
51
] and has a role in the
neurotransmission of pain and noxious stimuli in the spinal cord [
52
]. It has been described
in numerous cell-type SP products, e.g., macrophages, eosinophils, lymphocytes, and den-
dritic cells [
53
,
54
]. The SP-induced release of inflammatory mediators, such as cytokines,
oxygen radicals, and histamine, enhances tissue damage and stimulates further recruit-
ment of leukocytes, thereby enhancing the inflammatory response [
55
]. SP induces local
vasodilation and changes the vascular permeability, thereby increasing the delivery and
accumulation of leukocytes into tissues to express local immune responses [
56
]. SP often
co-expresses with other transmitter molecules, like CGRP and glutamate in the TG and
trigeminal nucleus caudalis [
57
,
58
]. During the headache phase of migraine, a significant
increase in plasma SP and CGRP levels is demonstrated [59].
Moreover, PACAP is found in several structures that are relevant to the pathomecha-
nism of migraine, e.g., in the dura mater, the cerebral vessels [
60
], the TG [
61
], the TNC [
62
],
and the cervical spinal cord [
63
]. It was recently found that PACAP is co-expressed with
CGRP in some dural nerve fibers [
64
]. PACAP plays a role in neuromodulation, neurogenic
inflammation, and nociception [
65
], and in addition, it is involved in the higher-order
processing of pain in brain regions such as the thalamus and the amygdala [
66
,
67
]. PACAP
is also relevant in the central sensitization and emotional load of pain [
68
]. Zhang and col-
leagues found that following inflammation in sensory neurons, PACAP is upregulated [
69
].
Meningeal sensory fibers can release neuropeptides from their peripheral endings in the
meninges, where they can evoke components of neurogenic inflammation [64].
Biomedicines 2022,10, 76 5 of 25
VIP is widely distributed in the central and peripheral nervous systems [
70
]. VIP
plays as potent vasodilators, acting on the smooth muscle cells in arterioles [
71
]. VIP can
modulate mast cell degranulation and the production of proinflammatory cytokines, such
as interleukins, including IL-6 and IL-8 [
72
]. In a clinical study, during the interictal period
of chronic migraine, higher VIP levels have been reported in peripheral venous blood than
in control subjects [
73
]. Pellesi et al. observed that as opposed to shorter vasodilation,
prolonged VIP-mediated vasodilation causes more headaches [
74
]. Together, VIP may
contribute to migraine pain through vasodilation and dural mast cell degranulation.
Transient receptor potential vanilloid-1 receptor (TRPV1), a nonselective cation chan-
nel, is a molecular component of pain detection and modulation [
75
]. TRPV1 receptors are
present in the human TG [
76
] and trigeminal afferents, which innervate the dura mater [
77
].
In addition to excessive heat, various exogenous and endogenous triggering factors can
directly activate or sensitize TRPV1 [
78
]. TRPV1 activation leads to the release of neu-
ropeptides, such as SP and CGRP, which can cause vasodilation and initiate neurogenic
inflammation within the meninges [
79
]. TRPV1 activation and/or sensitization can enhance
inflammatory responses via the expression and release of other inflammatory mediators.
Histamine plays a role in migraine; it can modulate neurogenic inflammation and
nociceptive sensitization [
80
]. During a migraine attack, elevated levels of a histamine
precursor histidine were found in plasma and cerebrospinal fluid (CSF) [
81
], and the
histamine levels of the plasma were increased both ictally and interictally in migraine
patients [
80
]. The release of SP contributes to local vasodilation, induces histamine release
from mast cells, and produces flare and further activates other sensory nerve endings [
82
].
C-fibers are known to be activated by histamine and are responsible for the neuropeptide
release. Nerve fibers, which contain histamine, have been found in the superficial laminae
of the dorsal horn, an essential site for nociceptive transmission [
83
]. In inflammatory
conditions, histamine can mediate the release of SP and glutamate [84] (Table 1).
Table 1.
Neuropeptides and neurotransmitters and their role in migraine and neurogenic inflammation.
Neuropeptides/
Neurotransmitters Receptors Migraine/Neurogenic Inflammation-Related
Functions References
CGRP CLR, RAMP1
craniocervical vasodilation,
peripheral and central sensitization,
neuron-glia interaction,
involved plasma extravasation,
mast cell degranulation,
Asghar et al., 2011 [44],
Holzer, 1998 [45],
Ottosson and Edvinsson, 1997 [46],
Lennerz et al., 2008 [47],
Raddant and Russo, 2011 [48]
SP NK1 craniocervical vasodilation,
plasma protein extravasation,
cytokines, oxygen radicals, and histamine release
Hökfelt et al., 1975 [49],
Ribeiro-da-Silva and Hökfelt, 2000 [50],
Snijdelaar et al., 2000 [51],
Graefe and Mohiuddin, 2021 [52],
Killingsworth et al., 1997 [53],
Weinstock et al., 1988 [54],
Holzer and Holzer-Petsche, 1997 [55],
Pernow, 1983 [56],
Gibbins et al., 1985 [57],
Battaglia and Rustioni, 1988 [58],
Malhotra, 2016 [59]
PACAP PAC1, VPAC1, VPAC2 craniocervical vasodilation,
peripheral and central sensitization
Jansen-Olesen and Hougaard Pedersen,
2018 [60],
Eftekhari et al., 2013 [61],
Nielsen et al., 1998 [62],
Jansen-Olesen et al., 2014 [63],
Uddman et al., 2002 [64],
Hashimoto et al., 2006 [65],
Martin et al., 2003 [66],
Missig et al., 2014 [67],
Kaiser and Russo, 2013 [68],
Zhang et al., 1998 [69]
Biomedicines 2022,10, 76 6 of 25
Table 1. Cont.
Neuropeptides/
Neurotransmitters Receptors Migraine/Neurogenic Inflammation-Related
Functions References
VIP VPAC1, VPAC2 craniocervical vasodilation,
mast cell degranulation,
IL-6 and IL-8 production
Kilinc et al., 2015 [70],
Ohhashi et al., 1983 [71],
Kakurai et al., 2001 [72],
Cernuda-Morollón et al., 2014 [73],
Pellesi et al., 2020 [74]
- TRPV1
vasodilation,
peripheral and central sensitization,
neuropeptide release (SP, CGRP)
initiate neurogenic inflammation
Caterina et al., 2000 [75],
Quartu et al., 2016 [76],
Dux et al., 2020 [77],
Bevan et al., 2014 [78],
Meents et al., 2010 [79]
histamine H1–4Rvasodilation,
mediate SP and glutamate release
Yuan and Silberstein, 2018 [80],
Castillo et al., 1995 [81],
Heatley et al., 1982 [82],
Foreman et al., 1983 [83],
Rosa and Fantozzi, 2013 [84]
4. Neurogenic Inflammation
The localized form of inflammation is neuroinflammation, which occurs in both the
peripheral and CNSs. The main features of NI are the increased vascular permeability,
leukocyte infiltration, glial cell activation, and increased production of inflammatory medi-
ators, such as cytokines and chemokines [
85
]. NI increases the permeability of the blood
to the brain barrier, thus allowing an increased influx of peripheral immune cells into the
CNS [86] (Figure 2A).
Biomedicines 2022, 10, x FOR PEER REVIEW 7 of 27
Figure 2. Neurogenic inflammation and its main features. (A) Stimulation of the trigeminal nerve
causes the release of neuropeptides, including CGRP, SP, NO, VIP, and 5-HT, leading to neuro-
genic inflammation, which has four main features: the increased vascular permeability, leukocyte
infiltration, glial cell activation, and increased production of inflammatory mediators, such as cy-
tokines and chemokines. (B) Vasoactive peptides, such as CGRP and SP, bind their receptors on
smooth muscle of dural vessels and cause vasodilation. The released neuropeptides induce mast
cell degranulation, resulting in the release of histamine, which leads endothelium-dependent vas-
odilation. (C) Binding of the released SP to the NK1 receptors expressed on the microvascular
Figure 2. Cont.
Biomedicines 2022,10, 76 7 of 25
Biomedicines 2022, 10, x FOR PEER REVIEW 7 of 27
Figure 2. Neurogenic inflammation and its main features. (A) Stimulation of the trigeminal nerve
causes the release of neuropeptides, including CGRP, SP, NO, VIP, and 5-HT, leading to neuro-
genic inflammation, which has four main features: the increased vascular permeability, leukocyte
infiltration, glial cell activation, and increased production of inflammatory mediators, such as cy-
tokines and chemokines. (B) Vasoactive peptides, such as CGRP and SP, bind their receptors on
smooth muscle of dural vessels and cause vasodilation. The released neuropeptides induce mast
cell degranulation, resulting in the release of histamine, which leads endothelium-dependent vas-
odilation. (C) Binding of the released SP to the NK1 receptors expressed on the microvascular
Figure 2.
Neurogenic inflammation and its main features. (
A
) Stimulation of the trigeminal nerve
causes the release of neuropeptides, including CGRP, SP, NO, VIP, and 5-HT, leading to neurogenic
inflammation, which has four main features: the increased vascular permeability, leukocyte infiltra-
tion, glial cell activation, and increased production of inflammatory mediators, such as cytokines and
chemokines. (
B
) Vasoactive peptides, such as CGRP and SP, bind their receptors on smooth muscle of
dural vessels and cause vasodilation. The released neuropeptides induce mast cell degranulation,
resulting in the release of histamine, which leads endothelium-dependent vasodilation. (
C
) Binding
of the released SP to the NK1 receptors expressed on the microvascular blood vessels disrupts the
membrane and causes plasma protein leakage and leukocyte extravasation. (
D
) Mast cells are in close
association with neurons, especially in the dura, where they can be activated following trigeminal
nerve and cervical or sphenopalatine ganglion stimulation. Release of neuropeptides causes mast
cell degranulation, which leads to release of histamine and serotonin and selectively can cause the
release of pro-inflammatory cytokines, such as TNF-
α
, IL-1, and IL-6. (
E
) Under the influence of
inflammatory stimuli, microglia can become reactive microglia. Microglia activation leads to the
production of inflammatory mediators and cytotoxic mediators.
The concept of NI was introduced by the experiment of Goltz and Bayliss, in which
skin vasodilation was observed during electrical stimulation of the dorsal horn, which could
not be linked to the immune system [
87
,
88
]. Dalessio was the first who hypothesized a
connection between NI and migraine and believed that a headache is a result of vasodilation
of cranial vessels associated with local inflammation [
89
]. This theory was later reworked
by Moskowitz, who believed that upon activation, the neuropeptide release from trigeminal
neurons has a role in increasing vascular permeability and vasodilation [90].
There are several theories concerning the mechanism of NI. Hormonal fluctuations or
cortical spreading depression can initiate two types of processes: activating the TS to trigger
the liberation of neuropeptides from the peripheral trigeminal afferents and/or degranulat-
ing the mast cells that can lead to the release of neuropeptides by activating and sensitizing
the nociceptors [
91
]. In rats, Bolay and colleagues demonstrated that after local electrical
stimulation of the cerebral cortex, CSD is generated, and it can trigger trigeminal activation,
Biomedicines 2022,10, 76 8 of 25
which causes meningeal inflammation occurring after the CSD disappearance [
92
]. Both
CGRP and SP play an important role in the development of NI. Released peptides, such as
CGRP, bind to its receptor on smooth muscle cells, eliciting a vasodilatory response, thereby
increasing meningeal blood flow in the dural vasculature. In contrast to CGRP, binding
of the released SP to the NK1 receptors expressed on the microvascular blood vessels
disrupts the membrane and causes plasma protein leakage. Both neuropeptides can induce
mast cell degranulation through their specific receptors and further sensitize meningeal
nociceptors [
91
]. The meningeal nerve fibers also contain neurotransmitters (e.g., glutamate,
serotonin) and hormones (e.g., prostaglandins) that can affect the activation and release of
neuropeptides, causing neurogenic inflammation [
89
]. Moreover, several cell types (e.g.,
endothelial cells, mast cells, and dendritic cells) can release tumor necrosis factor alpha
(TNF
α
), interleukins, nerve-growth factor (NGF), and VIP, also causing plasma protein
extravasation (PPE) [
93
,
94
], which is a key characteristic of NI. In addition, neuronal nitric
oxide synthase (nNOS) enzyme can be detected in the trigeminal nerve endings, the dural
mastocytes, and also the TNC and the TG [
95
], which catalyzes the synthesis of retrograde
signaling molecule nitric oxide (NO). NO has a major role in mediating many aspects of
inflammatory responses; NO can affect the release of various inflammatory mediators from
cells participating in inflammatory responses (e.g., leukocytes, macrophages, mast cells,
endothelial cells, and platelets) [
96
]. Through its retrograde signaling action, astrocytes
can influence the release of CGRP, SP, and glutamate [
97
,
98
]. Beside this, bradykinin and
histamine induce NO release from vascular endothelial cells, suggesting a strong interaction
between NO and inflammation [
99
]. The inflammation can lead to CGRP release from the
activated primary afferent neurons, which force satellite glial cells to release NO. NO can
induce nNOS, which can be considered a significant marker of the sensitization process of
the TS. TRPV channels permit afferent nerves to detect thermal, mechanical, and chemical
stimuli, thereby regulating NI and nociception [
100
]. TRPV1 was identified in dorsal root
ganglion (DRG), TG neurons, and spinal and peripheral nerve terminals [
101
]. Inflamma-
tory mediators remarkably up-regulate TRPV1 through activation of phospholipase C (PLC)
and protein kinase A (PKA) and protein kinase C (PKC) signaling pathways [
102
–
105
].
Increased TRPV1 expression in peripheral nociceptors contributes to maintaining inflam-
matory hyperalgesia [
101
]. In an experimental injury model, Vergnolle et al. demonstrated
that a decrease in osmolarity of extracellular fluid could induce neurogenic inflammation,
which TRPV4 can mediate [
106
]. Furthermore, plasma and cerebrospinal fluid levels of
neuropeptides, histamine, proteases, and pro-inflammatory cytokines (e.g., TNF
α
, IL-1
β
)
are elevated during migraine attacks [
107
,
108
], suggesting that neuroimmune interactions
contribute to migraine pathogenesis.
4.1. Vasodilation
There are various cell types in blood vessels that both release and respond to numerous
mediators that can contribute to migraine; this includes growth factors, cytokines, adeno-
sine triphosphate (ATP), and NO [
109
–
112
]. In the central system, NO may be involved in
the regulation of cerebral blood flow and neurotransmission [
59
]. NO can stimulate the
release of neuropeptides and causes neurogenic vasodilation [
113
]. In addition to NO, NGF
also increases the expression of CGRP and enhances the production and release of neu-
ropeptides, including SP and CGRP, in sensory neurons [
114
]. CGRP, a potent vasodilator,
is released from intracranial afferents during migraine attacks. This vasodilatory effect of
CGRP is mediated by its action on CGRP receptors, which stimulates the adenyl cyclase and
increases cyclic adenosine monophosphate (cAMP), thus producing potent vasodilation via
the direct relaxation of vascular smooth muscle [
115
,
116
]. In response to prolonged noxious
stimuli, SP is released from trigeminal sensory nerve fibers around dural blood vessels,
leading to endothelium-dependent vasodilation [
82
]. VIP also contributes to neurogenic
inflammation by inducing vasodilation [117] (Figure 2B).
Biomedicines 2022,10, 76 9 of 25
4.2. Plasma Protein Extravasation
Another critical feature of neurogenic inflammation is PPE. Based on preclinical
studies, the neurogenic PPE plays a role in the pathogenesis of migraine [
118
]. In several
studies, following electrical stimulation of the trigeminal neurons or intravenous capsaicin,
the peripheral nerve endings in the dural vasculature released SP, which caused plasma
protein leakage and vasodilation through the NK-1 receptors [
119
]. Transduction of the
SP signal through the NK1 receptor occurs via G protein signaling and the secondary
messenger cAMP, ultimately leading to the regulation of ion channels, enzyme activity, and
alterations in gene expression [
120
]. SP can indirectly influence plasma extravasation by
activating mast cell degranulation, which results in histamine release [
83
]. In addition, NKA
is able to induce plasma protein efflux and activate inflammatory cells [121] (Figure 2C).
4.3. Mast Cell Degranulation
It is well known that dural mast cells play a role in the pathophysiology of mi-
graine [
122
]. Meningeal mast cells are in close association with neurons, especially in the
dura, where they can be activated following trigeminal nerve and cervical or sphenopala-
tine ganglion stimulation [
123
]. The release of neuropeptides, such as CGRP, PACAP, and SP,
from meningeal nociceptors can cause the degranulation of mast cells [
124
], resulting in the
release of histamine and serotonin and selectively can cause the release of pro-inflammatory
cytokines, such as TNF-
α
, IL-1, and IL-6 [
125
–
127
]. The plasma and CSF levels of these
mediators (e.g., CGRP, TNF
α
, and IL-1
β
) are enhanced during migraine attacks [
104
]. VIP
promotes degranulation of mast cells [
128
], similar to the effects of SP [
83
]. It was found
that CSD can induce intracranial mast cell degranulation and promote the activation of
meningeal nociceptors [
129
,
130
]. Besides these, according to several studies, mast cells can
be activated by acute stress [
123
,
131
,
132
], which is known to precipitate or exacerbate mi-
graines [
133
,
134
]. Based on these findings, mast cells in themselves may promote a cascade
of associated inflammatory events resulting in trigeminovascular activation (Figure 2D).
4.4. Microglia Activation
Microglia appears in the CNS and can exert neuroprotective and neurotoxic effects as
well. Under the influence of inflammatory stimuli, microglia can become efficient mobile ef-
fector cells [
135
]. Microglia activation leads the production of inflammatory mediators and
cytotoxic mediators (e.g., NO, reactive oxygen species, prostaglandins) [
136
,
137
], which
might disrupt the integrity of the blood brain barrier, thereby allowing leukocyte migration
into the brain [
138
]. Microglia express receptors for neurotransmitters, such as glutamate,
gamma- aminobutyric acid, noradrenaline, purines, and dopamine [
139
]. It has been de-
scribed that activation of ion channels is related to the activation of microglia; therefore,
neurotransmitters probably influence microglia function [
140
]. Glutamate leads to neuronal
death but is also an activation signal for microglia [
141
]. Activation of glutamate receptors
causes the release of TNF-
α
, which, with microglia-derived Fas ligand, leads to neurotoxic-
ity [
142
]. Besides this, Off signals from neurons appear important in maintaining tissue
homeostasis and limiting microglia activity under inflammatory conditions, presumably
preventing damage to intact parts of the brain [
143
]. Endothelin B-receptor-mediated regu-
lation of astrocytic activation was reported to improve brain disorders, such as neuropathic
pain [
144
]. SP also directly activates microglia and astrocytes and contributes to microglial
activation [
145
,
146
], initiating signaling via the nuclear factor kappa B pathway, leading to
pro-inflammatory cytokines production [147] (Figure 2E).
4.5. Cytokines, Chemokines
Cytokines are small proteins produced by most cells in the body, which possess
multiple biologic activities to promote cell-cell interaction [
148
]. There is evidence that
cytokines play an important role in several physiological and pathological settings, such
as immunology, inflammation, and pain. [
149
]. The most important pro-inflammatory
cytokines include IL-1, IL-6, and TNF
α
, and the key chemokine is IL-8 [
149
]. Cytokines
Biomedicines 2022,10, 76 10 of 25
and chemokines are released by neurons, microglia, astrocytes, macrophages, and T cells,
and these factors might activate nociceptive neurons [
150
]. TNF
α
can trigger tissue edema
and immune cell infiltration [
151
] and can influence the reactivity of signal nociceptors
to the brain and increase blood levels during headaches, playing a crucial role in the
genesis of migraine [
152
]. Cytokines are considered to be pain mediators in neurovascular
inflammation, which generates migraine pain [
153
]. They can induce sterile inflammation
of meningeal blood vessels in migraines [
154
]. Besides this, elevated levels of chemokines
can stimulate the activation of trigeminal nerves and the release of vasoactive peptides;
thereby, they can induce inflammation [
155
]. Based on these, cytokines and chemokines
might contribute to migraine.
5. Animal Models of Neurogenic Inflammation
Developing animal models of human illnesses is a challenging task for translational re-
search, but it is indispensable to understanding pathomechanism, searching for biomarkers,
and engineering novel treatment [
156
–
164
]. Migraine research is no exception. Chemical
activation of meningeal trigeminal nociceptors is possible in animal experiments. The use
of Complete Freund’s adjuvant (CFA, dried and inactivated Mycobacterium tuberculo-
sis in mineral oil) or inflammatory soup (IS, a standard mixture of histamine, serotonin,
bradykinin, and prostaglandin E2) on the surface of the dura mater is a useful method for
inducing trigeminal activation and sensitization and developing neurogenic inflammation
in rats [
165
–
167
]. It has been shown that trigeminal brainstem neurons have been sensitive
to both subarachnoid superfusion and topical IS administration [
37
,
168
]. Lukács et al.
demonstrated that the application of CFA or IS onto the dural surface can induce changes
in the expression of phosphorylated extracellular signal-regulated kinase
1
2
(pERK1/2),
IL-1
β
, and CGRP-positive nerve fibers in the TG [
167
]. Similar to the previous experiment,
Laborc et al. used topical administration of IS or CFA on the dura mater to examine the
activation pattern that is caused by chemicalstimulation, and they found that application
of IS on the dura mater induces short-term c-Fos activation, while CFA did not cause
any difference in the number of c-Fos-positive cells between the CFA-treated and control
groups. Whereas short survival times were used, the authors believe this may have been
the reason that the CFA did not prove effective [
169
]. Spekker et al. found that IS was
able to cause sterile neurogenic inflammation in the dura mater and increased the area
covered by CGRP and TRPV1 immunoreactive fibers and the number of neuronal nitric
oxide synthase (nNOS)-positive cells in the TNC, and pretreatment with sumatriptan or
kynurenic acid (KYNA) could modulate the changes caused by IS. Sumatriptan probably
acted through the 5-HT
1B/1D
receptors, while KYNA possibly acted predominantly by
inhibiting the glutamate system and thereby blocking sensitization processes, which is
important in migraine [
170
]. Furthermore, Wieseler and colleagues observed an increase in
the level of IL-1
β
and TNF
α
, and the microglial/macrophage activation marker CD11b in
Sp5C after IS was administered bilaterally through supradural catheters in freely moving
rats [171].
In addition to morphological changes, IS can also influence animal behavior. Oshinsky
and Gomonchareonsiri used IS treatment three times per week for up to four weeks,
and they demonstrated that repeated infusions of IS over weeks induced a long-lasting
decrease in periorbital pressure thresholds [
172
]. Melo-Carrillo and colleagues described
that repeated infusion of IS increased the resting and freezing behavior and decreased the
locomotor activity [
173
]. These observations are consistent with decreased routine physical
activity and lack of exercise due to migraine-induced pain in migraine patients [
174
].
Moreover, they found a specific ipsilateral facial grooming behavior, which may be related
to the unilateral nature of migraine. In an animal model of intracranial pain, Malick et al.
showed that simultaneous chemical and mechanical stimulation of the dura mater not only
increases the number of Fos-positive neurons in the medullary dorsal horn but can reduce
the appetite of the rats. [
175
]. Wieseler et al. experienced facial and hind paw allodynia and
after two IS infusions [
176
]. In a novel large animal model of recurrent migraine, repeated
Biomedicines 2022,10, 76 11 of 25
chemical stimulation of the dura mater reduced locomotor behavior, which may mimic
a decrease in routine physical activity in people with headaches. In addition, increased
scratches and slow movements were observed; these may reflect pain localized to the head
area [
177
] (Figure 3). Based on these experiments, it can be said that dural application of IS
triggers activation and sensitization of the trigeminal system. Therefore, this is a relevant
animal model of acute migraine.
Biomedicines 2022, 10, x FOR PEER REVIEW 12 of 27
Figure 3. nNOS, pERK, ILs), increase the resting and freezing behavior, and decrease the appetite
and locomotor activity of the animals. In addition, it can enhance grooming and scratching behavior
and elicit mechanical and thermal hypersensitivity. CGRP, calcitonin gene-related peptide; TRPV1,
transient receptor potential vanilloid receptor; nNOS, neuronal nitric-oxide synthase; IL, interleu-
kins; pERK, phosphorylated extracellular signal-regulated kinase.
6. Current Treatments and Advances in Preclinical Research
Triptans are widely used to relieve migraine attacks; acting as agonists on 5-hydrox-
ytryptamine receptors (5-HT1B/1D), they can cause the constriction of dilated cranial arteries
and the inhibition of CGRP release [178]. In an animal model of migraine, after electrical
stimulation of the TG, sumatriptan attenuates PPE by preventing the release of CGRP
[179]. In knockout mice and guinea pigs, it has been shown that 5-HT1D receptors have a
role in the inhibition of neuropeptide release, thereby modifying the dural neurogenic
inflammatory response [180]. The use of triptans is limited by their vasoconstrictive prop-
erties. As triptans are not effective in everyone, they often lead to medication overuse,
triggering migraine to become chronic (Table 2).
Ditans target the 5-HT1F receptor, which is expressed in the cortex, the hypothalamus,
the trigeminal ganglia, the locus coeruleus, the middle cerebral artery, and the upper cer-
vical cord. Lasmiditan is the first drug approved for clinical use. Contrary to triptans, Las-
miditan does not cause vasoconstriction. The activation of 5-HT1F receptor inhibits the re-
lease of CGRP and probably SP from the peripheral trigeminal endings of the dura and
acts on the trigeminal nucleus caudalis or the thalamus [181].
Besides triptans and ditans, acute treatments of migraine headaches, i.e., ergot alka-
loids and nonsteroidal anti-inflammatory agents (NSAIDs), may decrease the neurogenic
Figure 3.
nNOS, pERK, ILs, increase the resting and freezing behavior, and decrease the appetite
and locomotor activity of the animals. In addition, it can enhance grooming and scratching behavior
and elicit mechanical and thermal hypersensitivity. CGRP, calcitonin gene-related peptide; TRPV1,
transient receptor potential vanilloid receptor; nNOS, neuronal nitric-oxide synthase; IL, interleukins;
pERK, phosphorylated extracellular signal-regulated kinase.
6. Current Treatments and Advances in Preclinical Research
Triptans are widely used to relieve migraine attacks; acting as agonists on 5-hydroxy-
tryptamine receptors (5-HT
1B/1D
), they can cause the constriction of dilated cranial arteries
and the inhibition of CGRP release [
178
]. In an animal model of migraine, after electrical
stimulation of the TG, sumatriptan attenuates PPE by preventing the release of CGRP [
179
].
In knockout mice and guinea pigs, it has been shown that 5-HT
1D
receptors have a role in the
inhibition of neuropeptide release, thereby modifying the dural neurogenic inflammatory
Biomedicines 2022,10, 76 12 of 25
response [
180
]. The use of triptans is limited by their vasoconstrictive properties. As
triptans are not effective in everyone, they often lead to medication overuse, triggering
migraine to become chronic (Table 2).
Table 2. Current treatments and advances in preclinical research.
Drug Class Drug Target FDA Appoved
NSAIDs
Acetylsalicylic acid
COX1–2
yes
Ibuprofen yes
Diclofenac potassium yes
Paracetamol yes
Triptans
Sumatriptan
5-HT1D receptor
yes
Zolmitriptan yes
Almotriptan yes
Rizatriptan yes
Frovatriptan yes
Naratriptan yes
Eletriptan 5-HT1B/1D receptor yes
Ditans Lasmiditan 5-HT1F receptor yes
Gepants
Ubrogepant
CGRP receptor
yes
Rimegepant yes
Atogepant no
Vazegepant no
Ergot alkaloids Ergotamine tartrate α-adrenergic
receptor,5-HT receptors yes
CGRP/CGRP receptor
monoclonal antibody
Erenumab CGRP receptor yes
Eptinezumab
CGRP ligand
yes
Fremanezumab yes
Galcenezumab yes
NK1R antagonists Aprepitant NK1 receptor yes
PACAP/PAC1 receptor
monoclonal antibody
ALD1910 PACAP38 no
AMG-301 PAC1 receptor no
Endocannabinoids 2-Arachidonoylglycerol CB1 receptor no
Anandamide CB1 receptor no
Ditans target the 5-HT
1F
receptor, which is expressed in the cortex, the hypothalamus,
the trigeminal ganglia, the locus coeruleus, the middle cerebral artery, and the upper
cervical cord. Lasmiditan is the first drug approved for clinical use. Contrary to triptans,
Lasmiditan does not cause vasoconstriction. The activation of 5-HT
1F
receptor inhibits the
release of CGRP and probably SP from the peripheral trigeminal endings of the dura and
acts on the trigeminal nucleus caudalis or the thalamus [181].
Besides triptans and ditans, acute treatments of migraine headaches, i.e., ergot alka-
loids and nonsteroidal anti-inflammatory agents (NSAIDs), may decrease the neurogenic
inflammatory response [
182
]. NSAIDs have anti-inflammatory, analgesic, and anti-pyretic
properties. Their primary effect is to block the enzyme cyclooxygenase and hence mitigate
prostaglandin synthesis from arachidonic acid [
183
]. Both acetaminophen and ibuprofen,
which can reduce pain intensity, can also be used in children. Magnesium pretreatment
increases the effectiveness of these treatments and reduces the frequency of pain [
184
]. Er-
Biomedicines 2022,10, 76 13 of 25
gotamine has been recommended to abort migraine attacks by eliminating the constriction
of dilated cranial blood vessels and carotid arteriovenous anastomoses, reducing CGRP re-
lease from perivascular trigeminal nerve endings, and inhibit the nociceptive transmission
on peripheral and central ends of trigeminal sensory nerves [185].
An alternative treatment strategy is the use of CGRP-blocking monoclonal antibodies.
Monoclonal antibodies have a number of positive properties: (1) a long half-life, (2) long
duration of action, and (3) high specificity [
186
]. Four monoclonal antibodies are currently
developing for migraine prevention: three against CGRP and one against the CGRP receptor.
The safety and tolerability of these antibodies are promising; no clinically significant
change in vitals, ECGs, or hepatic enzymes was observed. Blocking of CGRP function
by monoclonal antibodies has demonstrated efficacy in the prevention of migraine with
minimal side effects in multiple Phase II and III clinical trials [187].
Another alternative approach to treating the migraine attack by limiting neurogenic
inflammatory vasodilation is the blockade of CGRP receptors by selective antagonists.
Gepants were designed to treat acute migraines [
188
]. These bind to CGRP receptors and
reverse CGRP-induced vasodilation but were not vasoconstrictors per se [
189
]. Based on
these, gepants may be an alternative if triptans are contraindicated. Currently, two gepants
(Ubrogepant, Rimegepant) are available on the market, but several are in development.
In gene-knockout studies, the hypothesis the tachykinins are the primary mediators of
the PPE component of NI has been strengthened [
190
,
191
]. Following topical application of
capsaicin to the ear, the PPE was decreased in Tac1-deficient mice compared to wild-type
mice [
192
]. Following activation of the trigeminal system by chemical, mechanical, or
electrical stimulation, tachykinin Receptor 1 (TACR1) antagonists seem to be adequate
to blocking dural PPE [
193
]. However, lanepitant, a selective TACR1 antagonist, has no
significant effect on migraine-associated symptoms [
194
]; moreover, it was found ineffective
in a migraine prevention study [
195
]. The only currently available and clinically approved
NK1 receptor antagonist is aprepitant, which is used as an antiemetic to chemotherapy-
induced nausea in cancer patients [196].
In animal models, blockage of TRPV1 receptors was effective to reverse inflammatory
pain; however, TRPV1 antagonists produce some serious side effects, e.g., hyperther-
mia [
197
]. Clinical data suggest that TRPV1 antagonists might be effective as therapeutic
options for certain conditions, such as migraine and pain related to several types of diseases.
Hopefully, current clinical trials with TRPV1 receptor antagonists and future studies pro-
vide an answer as to the role of TRPV1 in inflammatory and neuropathic pain syndromes.
The anti-nociceptive effects of endocannabinoids are thought to be mediated mainly
through the activation of cannabinoid receptor type 1 (CB1) [
198
]. Localization of CB1
receptors along the trigeminal tract and trigeminal afferents [
199
,
200
] suggests that the
endocannabinoid system can modulate the neurogenic-induced migraine [
201
]. Clinical
data suggested that in migraine patients, the endocannabinoid levels are lower [
202
,
203
].
In animal models of migraine, endocannabinoids can reduce neurogenic inflammation.
Akerman et al. reported that capsaicin-induced vasodilation is less after intravenous
administration of anandamide (AEA); in addition, AEA significantly prevented CGRP- and
NO-induced vasodilation in the dura [
204
]. In a previous study, Nagy-Grócz and colleagues
observed that NTG and AEA alone or combined treatment of them affects 5-HTT expression,
which points out a possible interaction between the serotonergic and endocannabinoid
system on the NTG-induced trigeminal activation and sensitization phenomenon, which
are essential during migraine attacks [
205
]. These results raise the possibility that the AEA
has a CB1 receptor-mediated inhibitory effect on neurogenic vasodilation of trigeminal
blood vessels. Based on these, anandamide may be a potential therapeutic target for
migraine. Besides these, the presence of CB1 receptors in the brain makes them a target
for the treatment of migraine, blocking not only peripheral but also central nociceptive
traffic and reducing CSD. CB2 receptors in immune cells may be targeted to reduce the
inflammatory component associated with migraine.
Biomedicines 2022,10, 76 14 of 25
PACAP and its G-protein-coupled receptors, pituitary adenylate cyclase 1 receptor
(PAC1) and vasoactive intestinal peptide receptor 1/2 (VPAC1/2), are involved in var-
ious biological processes. Activation of PACAP receptors has an essential role in the
pathophysiology of primary headache disorders, and PACAP plays an excitatory role in
migraine [
206
]. There are two pharmacology options to inhibit PACAP: PAC1 receptor
antagonists/antibodies directed against the receptor or antibodies directed against the
peptide PACAP [
207
]. Studies of the PAC1 receptor antagonist PACAP (6–38) have proved
that antagonism of this receptor may be beneficial even during migraine progression [
208
].
PACAP38 and PAC1 receptor blockade are promising antimigraine therapies, but results
from clinical trials are needed to confirm their efficacy and side effect profile.
The tryptophan-kynurenine metabolic pathway (KP) is gaining growing attention
in search of potential biomarkers and possible therapeutic targets in various illnesses,
including migraine [
209
,
210
]. KYNA is a neuroactive metabolite of the KP, which affects
several glutamate receptors, playing a relevant role in pain processing and neuroinflam-
mation [
181
]. KYNA may block the activation of trigeminal neurons, affect the migraine
generators, and modulate the generation of CSD [
209
,
211
]. An abnormal decrease or in-
crease in the KYNA level can cause an imbalance in the neurotransmitter systems, and
it is associated with several neurodegenerative and neuropsychiatric disorders [
212
–
215
].
Based on human and animal data, the KP is downregulated under different headaches; thus,
possibly less KYNA is produced [
216
]. It is consistent with the theory of hyperactive NMDA
receptors, which play a key role in the development of central sensitization [
217
] and thus
in migraine pathophysiology. In an NTG-induced rodent model of migraine, Nagy-Grócz
et al. demonstrated a decrease in the expression of KP enzymes after NTG administra-
tion in rat TNC [
218
]. Interferons can control the transcription expression of indoleamine
2,3-dioxygenase (IDO), kynurenine 3-monooxygenase (KMO), and kynureninase (KYNU);
therefore, the pro-inflammatory cytokines may affect the kynurenine pathway [
219
]. It
is difficult for KYNA to cross the blood-brain barrier (BBB); therefore, synthetic KYNA
analogs may provide an additional alternative for synthesizing compounds that have
neuroprotective effects comparable to KYNA that can cross the BBB effectively. Preclin-
ical studies have shown the effectiveness of KYNA analogs in animal models of dural
stimulation [
220
,
221
]. Further preclinical studies are required to understand the role of
KYNA analogs in migraine and clinical studies that assess their effectiveness in acute or
prophylactic treatment (Figure 4).
In animal models of chronic pain and inflammation and several clinical trials, palmi-
toylethanolamide (PEA), endogenous fatty acid amide, has been influential on various
pain states [
222
–
224
]. In a pilot study, for patients suffering from migraine with aura,
ultra-micronized PEA treatment has been shown effective and safe [
225
]. Based on these,
PEA is a new therapeutic option in the treatment of pain and inflammatory conditions.
Biomedicines 2022,10, 76 15 of 25
Biomedicines 2022, 10, x FOR PEER REVIEW 16 of 27
Figure 4. Possible treatments of neurogenic inflammation and migraine. NSAIDs, non-steroidal
anti-inflammatory drugs; 5-HT, serotonin; CGRP, calcitonin gene-related peptide; COX, cyclooxy-
genase; Ab, antibody; NK1, neurokinin 1; TRPV1, transient receptor potential vanilloid receptor; SP,
substance P; EC, endocannabinoids; AEA, anandamide; 2-AG, 2-arachidonoylglycerol; CB, canna-
binoid receptor; THC, tetrahidrokanabinol; CBD, cannabidiol; NT, neurotransmitter; GLUT R, glu-
tamate receptors; α7AchR, alpha-7 nicotinic receptor; GPR35, G protein-coupled receptor 35; PA-
CAP, pituitary adenylate cyclase-activating polypeptide; PAC1R, pituitary adenylate cyclase 1 re-
ceptor.
7. Conclusion and Future Perspective
Migraines impose a tremendous negative impact on quality of life; nevertheless, an-
timigraine pharmacotherapy provides limited success in efficacy and tolerability. Mi-
graineurs and patients with chronic pain helplessly seek alternative or complementary
treatments, such as biofeedback, botox, yoga, acupuncture, acupressure, and music ther-
apy, among others [226]. The biggest challenge in antimigraine research may lie in com-
plex multifactorial pathogenesis of migraine headache, which is precipitated by inter-
winding genetic, endocrine, metabolic, and/or environmental factors, and thus, the exact
pathology leading to migraine attack remains poorly understood. This review article fo-
cuses on that migraine headache is a reflection of neurogenic inflammation in the activa-
tion and sensitization of trigeminovascular afferent nerves, which project to the second-
order neurons in the brainstem. The local release of neuropeptides and neurotransmitters
can not only cause the dilation of meningeal vessels but also induce neuroinflammation.
Figure 4.
Possible treatments of neurogenic inflammation and migraine. NSAIDs, non-steroidal anti-
inflammatory drugs; 5-HT, serotonin; CGRP, calcitonin gene-related peptide; COX, cyclooxygenase;
Ab, antibody; NK1, neurokinin 1; TRPV1, transient receptor potential vanilloid receptor; SP, sub-
stance P; EC, endocannabinoids; AEA, anandamide; 2-AG, 2-arachidonoylglycerol; CB, cannabinoid
receptor; THC, tetrahidrokanabinol; CBD, cannabidiol; NT, neurotransmitter; GLUT R, glutamate re-
ceptors;
α
7AchR, alpha-7 nicotinic receptor; GPR35, G protein-coupled receptor 35; PACAP, pituitary
adenylate cyclase-activating polypeptide; PAC1R, pituitary adenylate cyclase 1 receptor.
7. Conclusions and Future Perspective
Migraines impose a tremendous negative impact on quality of life; nevertheless,
antimigraine pharmacotherapy provides limited success in efficacy and tolerability. Mi-
graineurs and patients with chronic pain helplessly seek alternative or complementary
treatments, such as biofeedback, botox, yoga, acupuncture, acupressure, and music therapy,
among others [
226
]. The biggest challenge in antimigraine research may lie in complex
multifactorial pathogenesis of migraine headache, which is precipitated by interwinding
genetic, endocrine, metabolic, and/or environmental factors, and thus, the exact pathology
leading to migraine attack remains poorly understood. This review article focuses on that
migraine headache is a reflection of neurogenic inflammation in the activation and sensi-
tization of trigeminovascular afferent nerves, which project to the second-order neurons
in the brainstem. The local release of neuropeptides and neurotransmitters can not only
cause the dilation of meningeal vessels but also induce neuroinflammation. Animal models
Biomedicines 2022,10, 76 16 of 25
of migraine support this hypothesis that neurogenic inflammation plays a crucial role in
the sensitization process that leads to enhanced responsiveness of target tissues. However,
clinical study remains to be conducted. Understanding the signal transduction and regu-
lation of neuropeptides, including CGRP, SP, or neurokinin A, may open an approach to
discovery of new targets leading to the prevention of neurogenic inflammation.
Moreover, NI can be initiated by chronic stress, diet, hormonal fluctuations, or CSD.
The NI-triggering factors may become a possible interventional target preventing the initia-
tion of neuroinflammatory cascade. Immune reactions can also participate in NI. However,
little is known about the interaction of the immune system in NI. Understanding the mech-
anism of NI trigger is essential in migraine research. Migraine headache is frequently
observed in patients with cardiovascular diseases, respiratory diseases, psychiatric dis-
eases, and restless legs syndrome. The disturbance of the serotonergic nervous system, the
sympathetic nervous system, and the hypothalamic-pituitary-adrenal axis links migraine
to mood disorders and obesity. Thus, identifying predisposing factors precipitating to the
NI trigger may be a potential clue for a novel approach of migraine treatment.
Identification and usage of specific disease biomarkers can be suitable to guide the
treatment and monitor the improvement or worsening of migraine symptoms during the
treatment. MicroRNAs (miRs) may be useful as biomarkers of several diseases, including
pain conditions and migraine in both adults and children. Deregulation of miRNAs has
recently been described in migraine patients during attacks and pain-free periods [
227
]. In
addition, significant levels of some miRs have been demonstrated in the serum of migraine
children and adolescents without aura [
228
], suggesting that they are involved in the
pathogenetic mechanisms of migraine, further enhancing the role of these miRs in the
pathophysiology of migraine and their potential use as potential biomarkers.
We are untangling the puzzle of the mechanisms behind migraine attacks. However,
finding the initial cause and effective treatment remains far away. The translational animal
research currently tows forward the field of migraine research and may successfully serve
as a savior of migraineurs in the future.
Author Contributions:
Conceptualization, E.S.; writing—original draft preparation, E.S.; writing—
review and editing, E.S., M.T., Á.S. and L.V.; visualization, E.S.; supervision, L.V.; project adminis-
tration, L.V.; funding acquisition, M.T. and L.V. All authors have read and agreed to the published
version of the manuscript.
Funding:
The authors are funded by the Economic Development and Innovation Operational Pro-
gramme [GINOP 2.3.2-15-2016-00034; GINOP 2.3.2-15-2016-00048], National Research, Development
and Innovation Office [NKFIH-1279-2/2020 TKP 2020], TUDFO/47138-1/2019-ITM, and National
Scientific Research Fund [OTKA138125].
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: All figures were created with BioRender.com.
Conflicts of Interest:
The authors have no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
Abbreviations
α7AchR alpha-7 nicotinic receptor
2-AG 2-arachidonoylglycerol
AEA anandamide
ATP adenosine triphosphate
cAMP cyclic adenosine monophosphate
CB1 cannabinoid receptor type 1
CBD cannabidiol
Biomedicines 2022,10, 76 17 of 25
CFA Complete Freund’s adjuvant
CGRP calcitonin gene-related peptide
CNS central nervous system
CSD cortical spreading depression
CSF cerebrospinal fluid
DR nucleus raphe dorsalis
DRG dorsal root ganglion
GLUT R glutamate receptors
GPR35 G protein-coupled receptor 35
5-HT1B/1D 5-hydroxytryptamine receptors
IDO indoleamine 2,3-dioxygenase
IS inflammatory soup
KMO kynurenine 3-monooxygenase
KP tryptophan-kynurenine metabolic pathway
KYNA kynurenic acid
KYNU kynureninase
LC locus coeruleus
miRs microRNAs
NGF nerve-growth factor
NI neurogenic inflammation
NK1 neurokinin 1
NKA neurokinin A
nNOS neuronal nitric oxide synthase
NO nitric oxide
NPY neuropeptide Y
NRM nucleus raphe magnus
NSAIDs nonsteroidal anti-inflammatory agents
NT neurotransmitter
PAC1R pituitary adenylate cyclase 1 receptor
PACAP pituitary adenylate cyclase-activating polypeptide
PAG the periaqueductal grey matter
PEA palmitoylethanolamide
pERK phosphorylated extracellular signal-regulated kinase
PKA protein kinase A
PKC protein kinase C
PLC phospholipase C
PPE plasma protein extravasation
SP substance P
TACR1 tachykinin Receptor 1
TG trigeminal ganglion
THC tetrahidrokannabinol
TNC caudal trigeminal nucleus
TNFαtumor necrosis factor alpha
TRPV1 transient receptor potential vanilloid-1 receptor
TS trigeminal system
VIP vasoactive intestinal peptide
VPAC1/2 vasoactive intestinal peptide receptor 1/2
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