2021, 3(1):1-5 e-ISSN: 2674-7103

DOI: 10.37085/jmmv3.n1.2021.pp.1-5

Jornal Memorial

Medicina

Review

Use of capsaicin as a model in the study of migraine: a literature review

Raisa Ferreira Costa

Emanuela Paz Rosas

Daniella Araújo de Oliveira

Marcelo Moraes Valença

Postgraduate in Biological Sciences, Federal University of Pernambuco, Recife, Pernambuco, Brazil

Keizo Asami Immunopathology Laboratory, Federal University of Pernambuco, Recife, Pernambuco, Brazil

Department of Physiotherapy, Federal University of Pernambuco, Recife, Pernambuco, Brazil

Department of Neuropsychiatry, Federal University of Pernambuco, Recife, Pernambuco, Brazil

Abstract

Capsaicin is able to induce mast cell degranulation, an event probably related to the pathophys-

iology of a migraine attack. The present review study aimed to address the mechanisms of action

of capsaicin and other chemical inducers in mast cell degranulation and an interaction of nerves

and events that happen in the dura mater with the activation of mast cells. A survey was carried out

in the literature, from 1980 to 2019, in different databases, using the following terms: capsaicin,

mast cell and dura mater. 36 articles were selected for this review. Studies indicate that the main

mechanisms of action of capsaicin are chemical induction through the activation of TRPV1 chan-

nels, allowing calcium inux into neurons in the trigeminal ganglion of the dura mater, activating

mast cell degranulation, releasing pro-inammatory (e.g., histamine, oxide nitric) and vasoactive

(e.g., CGRP and substance P) substances. Therefore, the use of capsaicin may be a tool to be

used in an animal model to better understand the pathophysiology of migraine.

Raisa Ferreira Costa

raissac0sta@hotmail.com

Edited by

Juliana Ramos Andrade

Keywords:

Migraine

Pathophysiology

Capsaicin

Received: January 14, 2021

Accepted: January 22, 2021

ASAA

Costa RF, Rosas EP, Oliveira DA, Valença MM

Use of capsaicin as a model in the study of migraine: a literature review

Introduction

he mast cells are present in the proximity of sensory nerve

bers in the rat dura mater.

There is an interaction be-

tween mast cells with C bers in the dura mater.

Vasodilation,

plasma leakage and degranulation of mast cells contribute

to the release of pro-inammatory substances in the dura

mater, probably related to migraine attacks.

3-5

The mast cell

degranulation has been suggested as an important element

of neurogenic inammation, as mast cells exclusively release

histamine when activated by the release of Calcitonin gene-re-

lated peptide (CGRP) at the trigeminal terminals.

6-8

Histamine

mediating CGRP receptors are likely to be located in mast

cells.

9-12

In addition to CGRP, histamine also interacts with

increased production of nitric oxide (NO) in the mast cells.

13-16

All three chemical mediators contribute to vasodilation and

neurogenic inammation.

Therefore, CGRP is able to release

histamine and increase NO production from meningeal mast

cells and act as a very potent vasodilator of intracranial

arteries, occupying a prominent position in the nociceptive

elements in the primary cascade of a headache attack.

The capsaicin is one of the chemicals used in animal studies

to activate the trigeminovascular system mimicking part of

the migraine pathophysiological process and serving as an

experimental model, as it is associated with the release of

neuropeptides, through the opening of cationic channels that

results in accumulation of intracellular calcium, and mast cell

activation.

These mast cells, through vasoactive mediators,

contribute to stimulation of the large cranial arteries resulting

in neurogenic inammation and this is essential for their in-

volvement in primary headaches.

19-21

Thus, this review aims

to deepen the knowledge about the mechanisms of action of

capsaicin and other chemical inducers in the involvement of

mast cell degranulation in a migraine attack.

Methods

This review was conducted with articles that used capsaicin

to activate mast cells, in addition to other chemical inducers

that demonstrated interaction between the dura mater and

mast cells. The search was carried out with articles published

between the years 1980 and 2019. Articles from SciELO,

U.S. National Library of Medicine and the National Insti-

tutes Health (PubMed) and Web of Science databases were

evaluated. As search strategy, the following terms were used:

"Capsaicin" and "mast cell" and "dura mater" selected in

consultation with the Medical Subject Headings (MeSH). The

inclusion criteria were experimental model studies in rats that

described the mechanisms of action of chemical inducers,

including capsaicin. Initially, the titles and abstracts of the

articles found were read. Then, the articles were read and,

nally, an additional search was carried out that tracked

reference lists of all identied articles.

Results

Of the total 50 articles found, 36 were selected for this review.

Discussion

Capsaicin in experimental animal models is used to induce

inammation via chemical stress that increase vascular per-

meability in the dura mater by activating mast cells caused

by the release of neuropeptides.

22,23

The transient potential of the cationic receptor of the V sub-

family member 1 (TRPV1) also known as the capsaicin re-

ceptor, it’s a channel that acts as a mediator to stress. After

activation of these channels, they contribute to the opening of

intracellular calcium and potassium output, leading to hyper-

polarization of trigeminal neurons and vasodilation through

the release of CGRP and substance P, neuromodulator that

facilitates inammatory processes. Thus, TRPV channels play

vital roles in the vasculature and an important mediator for

vascular responses.

24-,26

Baylie e Brayden

demonstrated

that stimulating actions increase the release of vasoactive

peptides. Szolcsanyi

analyzed the depletion of sensory

neurons by capsaicin and the relation of neuropeptides re-

leased in the analysis of the diameter of the cranial arteries,

to verify whether there was dilation. Huang et al.

observe

that chemical stimulation with capsaicin also inuences the

release of CGRP assessed immunohistochemically through

the polyclonal antibody of rabbits.

The activation of mast cells by capsaicin leads to degranu-

lation and the consequent release of pro-inammatory sub-

stances (histamine and nitric oxide). Histamine increases

CGRP levels released by C ber neurons and consequently

more numbers of degranulated mast cells, a positive feedback

cycle, and nitric oxide contributes to controlling the viability

of cranial arteries. In studies using capsaicin, it was observed

that in neonates rats, chemical stimulation destroyed the pepti-

dergic nerve endings, demonstrating that stresses in neonates

do not induce mast cell degranulation.

22,23

The stimulating action of capsaicin to increase the release of

neuropeptides causes depletion of sensory neurons, releasing

ASAA

Costa RF, Rosas EP, Oliveira DA, Valença MM

Use of capsaicin as a model in the study of migraine: a literature review

CGRP causing destruction of peptidergic nerve endings

in neonatal animals that do not have a consistent neural

structure. Dimtriadou et al. (1991) used capsaicin (50mg/kg;

48 h) administered subcutaneously in rats and do not had

statistical difference in mast cell degranulation of the dura

mater. Years later, with higher doses of capsaicin (50 mg/

kg, 1 day of life and 100 mg/kg, 3 days of life) there was a

statistical difference in the degranulation of mast cells of the

dura mater, due to the increase in the capsaicin dose.

28,29

Thus, neonates are not a good experimental model to mimic

the pathophysiology of migraine, because they do not have

a consistent and dened neural structure as in adult rats.

In studies with adult rats, capsaicin was able to induce a

dose-response in the histamine release and consequent ac-

tivation of mast cells, observing signicant degranulation

results.

As observed in another study that showed that foods

containing capsaicin are able to suppress neuropeptides such

as substance P that can cause the co-release of CGRP, since

they are often located in the same neuron, thus activating

the release of histamine in mast cells, mediating mast cell

activation.

This connection of mast cells with sensory neu-

rons in the dura mater has a bidirectional response, where

it signals responses with the nerves in relation to the external

environment and endogenous and exogenous substances

and degranulation in response to dural signals for the body's

immunity.

32,33

In adult rats, it was also shown, through other inducers, as

cholinergic agents (carbacol and nicotine); ovarian hormones

and compound 48/80, a polymer that promotes histamine

release, the percentage of degranulated mast cells in the

dura mater and its relationship with migraine. It was observed

that these chemical inducers had different mechanisms of

action to activate mast cells, presenting signicant results in

the percentage of degranulation and in the pathophysiology

of migraine.

In the study relating the ovarian hormones

(estradiol and progesterone) to the density of mast cells in

the dura mater and their potential role in headache, it is ob-

served that the application of estrogen, but not progesterone,

increases the density of mast cells.

34,35

In the study of differen-

tiating neuropeptides with vasoactive potentials, PACAP-38

to PACAP-27, in the dura mater and the frequency of mast

cell degranulation, it was found that the difference is not in

the pituitary adenylate cyclase-activating polypeptide type I

(PAC1) receptor but because PACAP38 has greater induction

in mast cell degranulation by acting via phospholipase C,

which presents enzymes that contribute to the opening of

intracellular calcium.

And in the study of cholinergic agents

in the activation of calcium channels sensitized by CGRP,

there is a relationship that suggests nociceptive regulation of

the meninges, providing ring to primary afferents assuming

that this is the source of the headache, causing a signicant

mast cell degranulation and inducing vasodilation in the dura

mater.

Then, other stimulants have mechanisms of action that

resemble capsaicin to degranulate mast cells and increase

the levels of these three inammatory mediators.

Thus, probably due to the actions of capsaicin, it is possible

to study the pathophysiology of the migraine by mast cell

degranulation. Mast cell degranulation was considered a

fundamental element for migraine physiopathology, as acti-

vation and consequent degranulation increases the plasma

levels of three chemical mediators (CGRP, histamine and nitric

oxide) that are related to vasodilation. Capsaicin, with its neu-

ron-stimulating action, opens calcium ion channels, leading

to neuron hyperpolarization and the release of vasoactive

neuropeptides, activating mast cells and causing vasodilation.

Conclusion

The method of inducing mast cell degranulation by chemi-

cal activation of capsaicin, and other inducers, mimics the

pathophysiological process of migraine by activating the

trigeminovascular system and neurogenic inammation.

Raisa Ferreira Costa

https://orcid.org/0000-0002-1180-6689

Emanuela Paz Rosas

https://orcid.org/0000-0001-9895-5654

Daniella Araújo de Oliveira

http://orcid.org/0000-0002-6013-978X

Marcelo Moraes Valença

https://orcid.org/0000-0003-0678-3782

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