Transient Receptor Potential Channel 4 Small-Molecule Inhibition Alleviates Migraine-Like Behavior in Mice

Cohen, Cinder Faith; Prudente, Arthur Silveira; Berta, Temugin; Lee, Sang Hoon

doi:10.3389/fnmol.2021.765181

Cited by 8 publications

(8 citation statements)

References 44 publications

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“…A recent study showed that TRPC4 is highly expressed in TG neurons and that pharmacological inhibition of TRPC4 significantly prevented migraine-linked cutaneous mechanical hypersensitivity and increased plasma levels of CGRP [133]. Specifically, we found that TRPC4 is highly expressed in TG tissues and neurons, with most of these neurons also expressing CGRP and innervating the skin.…”

Section: Trpc4 Channel As An Emerging Target For Antimigraine Drugssupporting

confidence: 54%

“…↓ mechanical allodynia; ↓ CGRP plasma levels [133] TRPV1, the first of many thermosensitive TRP channels to be identified, functions as a noxious heat sensor that is activated by temperatures greater than 42°C and pH changes [65,66]. Additionally, it is triggered by exogenous stimulants, such as capsaicin from chili peppers, and endogenous stimulants, such as anandamide produced in inflammatory processes [65][66][67].…”

Section: Trpm8mentioning

confidence: 99%

“…For instance, studies have shown that TRPC4 and TRPC5 are highly expressed in brain regions associated with anxiety and fear, and genetic silencing or pharmacological inhibition of these channels have been found to be effective in preclinical animal models of depression [129][130][131]. TRPC4 and TRPC5 are expressed not only in the brain but also in peripheral sensory neurons, where they are involved in axon guidance and sensory functions [132][133][134][135][136].…”

Section: Trpc4 Channel As An Emerging Target For Antimigraine Drugsmentioning

confidence: 99%

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Targeting Nociceptors and Transient Receptor Potential Channels for the Treatment of Migraine

Cohen¹,

Roh²,

Lee³

2023

Preprint

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Migraine is a neurovascular disorder that affects approximately 12% of the global population. While its exact causes are still being studied, researchers believe that nociceptors in the trigeminal ganglia play a key role in the pain signals of migraine. These nociceptors innervate the intracranial meninges and convey pain signals from the meninges to the thalamus. Targeting these nociceptors is considered promising due to their accessibility and distinct molecular profile, which includes the expression of several transient receptor potential (TRP) channels. These channels have been linked to various pain conditions, including migraine. This review discusses the role and mechanisms of nociceptors in migraine, the challenges of current antimigraine drugs, and the evidence for well-studied and emerging TRP channels, particularly TRPC4, as novel targets for migraine prevention and treatment.

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Section: Trpc4 Channel As An Emerging Target For Antimigraine Drugssupporting

confidence: 54%

Section: Trpm8mentioning

confidence: 99%

Section: Trpc4 Channel As An Emerging Target For Antimigraine Drugsmentioning

confidence: 99%

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Targeting Nociceptors and Transient Receptor Potential Channels for the Treatment of Migraine

Cohen¹,

Roh²,

Lee³

2023

Preprint

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“…Also, high plasmatic levels of CGRP have already been demonstrated in external jugular venous blood, saliva, and cerebrospinal fluid of migraine patients during an attack [3]. Besides, migraine animal model induce an increase in circulating CGRP levels in plasma [13,49], cerebrospinal fluid of the nestin/hRAMP1 transgenic mice [45]. Additionally, CGRP may trigger the release of pro-inflammatory cytokines [44], particularly IL-6 and TNF-α, which are also increased in the plasm of migraine patients [14,56].…”

Section: Discussionmentioning

confidence: 94%

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism

Viero

Rodrigues

Frare

et al. 2022

Preprint

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Background and purpose Migraine represents one of the major causes of disability worldwide and is more prevalent in women, it is also related to anxiety symptoms. Stress is a frequently reported trigger in migraine patients, such as sound stress, but the underlying mechanisms are not fully understood. However, it is known that patients with migraine have higher levels of plasma inflammatory cytokines and calcitonin gene-related peptide (CGRP). Stress mediated by unpredictable sound is already used as a model of painful sensitization, but migraine-like behaviors and sexual dimorphism have not yet been evaluated. This study characterized the nociception and anxiety-related symptoms after the induction of unpredictable sound stress in mice. Experimental approach C57BL/6 mice (20-30 g) were exposed to unpredictable sound stress for 3 days. Mainly, after 7 days of the last stress session mice developed hind paw, periorbital mechanical allodynia, grimacing pain behavior, anxiety-like, and reduced exploratory behavior. Key results These nociceptive and behavioral alterations detected in this model were shown mostly in female stressed mice. Besides, 7th-day post-stress nociception, these behaviors were consistently abolished by CGRP receptor antagonist olcegepant (BIBN4096BS, 100mg/kg by intraperitoneal route) until 3 h after treatment in stressed mice. In addition, we demonstrated an increase in levels of IL-6 and TNF-α and CGRP levels in stressed mice plasma, with female with higher levels when compared to male mice. Conclusions and implications This stress paradigm allows further preclinical investigation of mechanisms contributing to migraine pain, which appear to be distinct in male and female mice.

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“…Similarly, in rodents, pro-inflammatory cytokines were described as inductors of primary afferent nociceptors sensitization ( Khasar et al, 2008 ; Kursun et al, 2021 ) and high CGRP plasma levels have already been demonstrated in external jugular venous blood, saliva, and cerebrospinal fluid of migraine patients during an attack ( Alpuente et al, 2020 ). The migraine animal model also induces an increase in circulating CGRP levels in plasma ( Cohen et al, 2021 ; Sun et al, 2021 ) and cerebrospinal fluid of the nestin/hRAMP1 transgenic mice ( Recober et al, 2009 ). Additionally, CGRP may trigger the release of pro-inflammatory cytokines ( Ray et al, 2021 ), particularly IL-6 and TNF-α, which are also increased in the plasm of migraine patients ( Yücel et al, 2016 ; Conti et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism

et al. 2022

View full text Add to dashboard Cite

Migraine represents one of the major causes of disability worldwide and is more prevalent in women; it is also related to anxiety symptoms. Stress, such as sound stress, is a frequently reported trigger in migraine patients, but the underlying mechanisms are not fully understood. However, it is known that patients with migraine have higher levels of plasma inflammatory cytokines and calcitonin gene-related peptide (CGRP). Stress mediated by unpredictable sound is already used as a model of painful sensitization, but migraine-like behaviors and sexual dimorphism have not yet been evaluated. This study characterized nociception and anxiety-related symptoms after the induction of sound stress in mice. C57BL/6 mice (20–30 g) were exposed to unpredictable sound stress for 3 days, nonconsecutive days. We observed enhanced plasma corticosterone levels on day 1 after stress induction. First, 7 days after the last stress session, mice developed hind paw and periorbital mechanical allodynia, grimacing pain behavior, anxiety-like symptoms, and reduced exploratory behavior. The nociceptive and behavioral alterations detected in this model were mostly shown in female stressed mice at day 7 post-stress. In addition, on day 7 post-stress nociception, these behaviors were consistently abolished by the CGRP receptor antagonist olcegepant (BIBN4096BS, 100 mg/kg by intraperitoneal route) in female and male stressed mice. We also demonstrated an increase in interleukine-6 (IL-6), tumor necrosis factor (TNF-α), and CGRP levels in stressed mice plasma, with female mice showing higher levels compared to male mice. This stress paradigm allows further preclinical investigation of mechanisms contributing to migraine-inducing pain.

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Transient Receptor Potential Channel 4 Small-Molecule Inhibition Alleviates Migraine-Like Behavior in Mice

Cited by 8 publications

References 44 publications

Targeting Nociceptors and Transient Receptor Potential Channels for the Treatment of Migraine

Targeting Nociceptors and Transient Receptor Potential Channels for the Treatment of Migraine

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism

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