Headache Medicine 2020, 11(3):57-60 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.17

Headache Medicine

Review

The role of TRPM8 in the pathophysiology of migraine

Eduardo de Almeida Guimarães Nogueira Yara Dadalti Fragoso

MS & Headache Research,

Clinical Medicine and

Neuroimmunology, Headache, Santos, São Paulo, Brazil

Abstract

The transient receptor potential melastatin 8 (TRPM8) is a member of the mammal TRPM subfamily.

TRPM8 is involved in menthol-induced cold allodynia, a condition that activates the left lateral

thalamus and the primary and secondary somatosensory cortices, which are related to pain

processing. Cold is a well-known trigger of migraine. Thirty-nine articles were identied, 27 of

which were selected for review after reading the abstracts.

Fourteen papers were further excluded. TRPM8 seems to be involved in the pain mechanism of

migraine and therefore should be considered as a target for the development of therapies against

this type of primary headache.

Eduardo de Almeida Guimarães

Nogueira

eduagn@hotmail.com

Guaiaó 66 cj 2013, Santos, SP,

Brazil CEP 11035-260

Phone/Fax: +55 13 3273-6828.

Edited by

Mario Fernando Prieto Peres

Keywords:

TRPM8

Cation channels

Migraine disorders

Hyperalgesia

Headache

Physiopathology

Received: August 29, 2020

Accepted: September 30, 2020

ASAA

Nogueira EAG, Fragoso YD

The role of TRPM8 in the pathophysiology of migraine

Introduction

he transient receptor potential melastatin 8 (TRPM8) is

a member of the mammal TRPM subfamily.

TRPMs are

part of the transient receptor potential (TRP)family, a group

of 28 positively charged permeable ion channels expressed

in cell membranes and organelles.

TRPM8 acts as a sensor

in the cutaneous tissue for low temperatures leading to pain

and even allodynia when nervous injury occurs.

TRPM8

is involved in menthol-induced cold allodynia, a condition

that activates the left lateral thalamus and the primary and

secondary somatosensory cortices, which are related to pain

processing.

TRPM8 induces cold allodynia and, at the same time, it is

necessary for cooling/menthol-based analgesia.

Regarding

migraine, it is equally curious that cold temperatures can trig-

ger a migraine attack, while menthol can cause pain relief.

If TRPM8 is involved in the pathophysiology of migraine, it

might be by eliciting two different mechanisms or by involve

two different pathways.

According to Weyer and Letho

there are TRPM8 receptors in

humans’ dura mater that are stimulated when someone is ex-

posed to low temperatures causing activation of the trigeminal

pathway, releasing inammatory mediators such as Calcitonin

Gene Related Peptide (CGRP) and thus culminating in the

migraine crisis. The same authors also cite an experiment

carried out in rodents, in which the researchers administered

icilin to the animals' dura mater, causing migraine-mimicking

behaviors and when administering a channel antagonist, the

crisis disappeared. Another observation was the fact that the

administration of sumatriptan together with the TRPM8 ago-

nist did not cause the painful crisis. Very similar experiments

were made with CGRP decades ago. The complex formed

betweenTRPM8 channel and 5-HT1B receptor in primary

afferent neurons, may be responsible for the amplication of

the analgesic effect of TRPM8 activators and serotoninergical

agonists in tissue- and nerve-injury rat model.

Table 1. A summary of the main ndings of the 15 selected papers

Authors Year Conclusion

Bennemei S, Dussor G 2019 The repeated identication of TRPM8 variants in GWAS supports continued interest in this channel for the

disorder, but it remains unknown whether therapeutics should be agonists or antagonists

Chasman DI, Schürks M,

Anttila V et al.

2012 The association of rs10166942 may be stronger among women, which may be related to but would not

explain the higher prevalence of migraine in women

Chasman DI, Anttila V, Buring

JE, et al.

2014 TRPM8, the candidate gene for this SNP, is thought to mediate the sensation of pain rather than specic

neurological or vascular functions that might more directly differentiate the pathophysiology of the

migraine sub-classes

Dussor G, Cao YQ 2016 TRPM8 agonists and antagonists may be potential therapeutics, depending on how migraine is triggered

in individual patients. TRPM8 may be a novel target for personalized medicine in migraine treatment

Forstenpointner J, Binder A,

Maag R, et al.

2019 Experimental cold allodynia is mediated in different cerebral areas depending on the underlying

pathophysiology. The cold-induced inhibition of cold pain

Gonzalez-Muniz R, Bonache

MA, Martín-Escura C, Gomez-

Monterrey I.

2019 The location, expression or morphological changes of the TRPM8 channels in different tissues, such as

eyes, salivary glands, the brain, or the oropharyngeal system, among others, open new opportunities for

the treatment of diseases related to these systems

Kayama Y, Shibata M,

Takizawa T et al.

2017 TRPM8 activation can relieve migraine by suppressing TRPV1 activity. Facial TRPM8 appears to be a

promising therapeutic target for migraine

Ren L, Dhaka A, Cao YQ 2015 Activation of dural TRPM8 channels effectively inhibits meningeal irritation-evoked nocifensive behavior

in adult mice. This provides a foundation to further investigate the contribution of postnatal changes of

TRPM8-expressing dural afferents to the pathophysiology of pediatric and adult migraine

Samanta A, Hughes TET,

Moiseenkova-Bell VY

2018 TRP channels are crucial players in various other physiological and pathological conditions like cancer,

renal physiology, cardiac health and neuronal development. Therefore, most TRP channels are important

therapeutic targets

Viana F 2010 The identication of specic ion channels, especially TRP channels, involved in different pathophysiological

mechanisms including pain, pruritus, headache, chronic cough, and asthma, opens new opportunities for

their treatment

Viana F 2018 In healthy human subjects, menthol can change the perception of a previously innocuous temperature into

painful, suggesting a role of TRPM8 in cold pain However, menthol does not aggravate responses in

areas with a pre-existing cold allodynia, and can even result in an amelioration of symptoms

Weyer A, Letho SG 2017 Since chemotherapy is associated with changes in TRPM8 expression, perhaps TRPM8 antagonists

could be benecial in the prevention and/or reversal of this chemotherapy-induced cold allodynia. Or,

perhaps TRPM8 antagonists could still be useful therapeutics for any other cold-related painful allodynia or

hyperalgesia associated with other neuropathic or inammatory conditions or even migraine or bladder

pain

ASAA

Nogueira EAG, Fragoso YD

The role of TRPM8 in the pathophysiology of migraine

Methods

The authors performed a comprehensive review of the lit-

erature in the PubMed database, with the following terms:

“TRPM8” AND “Migraine”. The references of the selected

articles were explored for further potential papers. Inclusion

and exclusion of identied articles occurred after discussion

and agreement between both authors.

Results

Thirty-nine articles were identied, 27 of which were selected

for review after reading the abstracts. Eleven papers were

further excluded, as they were not related to the subject of this

review. One article in Chinese was excluded. A summary of the

main ndings of the 15 selected papers is presented in Table 1.

Discussion

The pathophysiology of migraine is still permeated with

mysteries, however genetic studies, increasingly shed some

light on this very interesting subject. The potential receptor

transient melastatin

is expressed at various sites in the human

body such as the eyes, brain, salivary glands, urinary system

and intestines. And for that reason it is believed that this ion

channel is involved in many different diseases, with migraine

being one of the most prevalent in the world.

It is known that in humans, TRPM8 is activated when exposed

to temperatures below 26°C, being a transducer of physical

stimuli in the peripheral sensitive bers of the skin and mucous

membranes. Cold is a well-known trigger of migraine.

The activation of the primary afferent neurons (PANs) that

innervate the dura mater and cerebral blood vessels is the

cornerstone of the pathogenesis of headaches. Regarding

that PANs of the dorsal root ganglia and trigeminal ganglion

(TG) also express, TRPM8 channels and CRGP, the stimulation

of TRPM8 channels by lower temperatures or cold induced

allodynia would activate primary afferent neurons of the

trigeminal pathway innervating the dura and cerebral vessels

triggering migraine attack.

Genome-wide association studies (GWAS) in humans showed

the association between migraine and TRPM8 activation has

mostly been observed in individuals from northern Europe.

There are three possible combinations of the TRPM8 Single

Nucleotide Polymorphism (SNP) rs10166942 in our genetic

code. They are: C;C or C;T or T;T alleles. Most of these

individuals from northern Europe carry the T; T allele of the

SNP rs10166942 which is the most associated with migraine

attacks.10 Those who carry the C; C or C; T alleles are at

lower risk for migraine.

Natural selection would be an explanation for this phenome-

non. People who expressed the T; T allele of SNP rs10166942

of TRPM8 in the meninges might be better adapted to the

environment in relations to those who do not express them.

Therefore, migraine may be interpreted as a price to pay for

this "evolutionary advantage".2 In addition, the prevalence

of rs10166942 seems to occur more often among women,

which may be linked to the higher frequency of migraine in

women.

11, 12

Interestingly, cooling agents such as menthol, icilin and euca-

lyptol act as agonists of TRPM8 but cause the effect of anal-

gesia and not pain. Dussor and Cao

proposed that the best

explanation for this would be the fact that these substances

also stimulate the activation of Transient Receptor Potential

Vanilloid 1 (TRPV1), concluding, therefore, that the activation

of TRPM8 alone is associated with the pain sensation, how-

ever when the activation occurs in concomitance with other

TRP channels, the body's response is analgesia.

According to Kayama et al.

, meningeal inammation acti-

vates TRPV1 trigeminal neurons. After meningeal inamma-

tion, TRPM8 expression is gradually upregulated through

transcriptional activation, which leads to increased concomi-

tant expression of TRPM8 and TRPV1. Some of these TRPM8/

TRPV1-positive neurons innervate the dura mater and face.

In this state, facial TRPM8 stimulation can reverse TRPV1-me-

diated thermal allodynia in a cell-autonomous manner. The

same authors9 carried an experience where TRPM8 agonists

attenuated the pain mediated by TRPV1 in the trigeminal path-

way suggesting that suggest that facial TRPM8 activation can

exert an analgesic action by down regulating TRPV1 function

at the level of trigeminal ganglia.

The development of new therapies for migraine targeting

TRPM8 requires further studies. It is not clear whether these

drugs should be agonists or antagonists of the ion channel

in question since, depending on the stimulus, both seem to

be able to alleviate the migraine attack.

It should be noted that TRPM8 and TRPV1 are also involved in

the pathophysiology of other craniofacial disorders, such as

meningitis. Therefore, the applicability of the present review

may extend beyond headaches.

ASAA

Nogueira EAG, Fragoso YD

The role of TRPM8 in the pathophysiology of migraine

Conclusion

TRPM8 seems to be involved in the pain mechanism of mi-

graine and therefore should be considered as a target for

the development of therapies against this type of primary

headache.

The Author's contribution: EAGN, data collection, method-

ology and writing; YDF, review, supervision and validation.

Financing: No

Conflict of interests: No

Eduardo de Almeida Guimarães Nogueira

https://orcid.org/0000-0002-6035-560X

Yara Dadalti Fragoso

https://orcid.org/0000-0001-8726-089X

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