Androgenic TRPM8 activity drives sexual dimorphism in a murine model of chronic migraine

Alarcón-Alarcón, David; Cabañero, David; Andrés-López, Jorge de; Fernández‐Ballester, Gregorio; Fernández-Carvajal, Asia; Ferrer-Montiel, Antonio

doi:10.21203/rs.3.rs-960579/v1

Cited by 3 publications

(3 citation statements)

References 39 publications

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“…Some studies have shown a sexual dimorphism in migraine-like models, with female rodents showing higher nociceptive and anxiety-like responses ( Araya et al, 2020 ). Recently, using a migraine model induced by nitroglycerin i. p. injection, a sexual dimorphic effect was detected, in which females had higher nociception than males ( Alarcón-Alarc ón et al, 2021 ). However, most of the studies using models of migraine have not evaluated sexual differences, and male mice or rats are normally tested ( Khasar et al, 2009 ; Taheri et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…Recently, using the migraine model induced by nitroglycerin i.p. injection, a sexual dimorphic effect was detected in which females had higher nociception than males [2]. However, most of the studies using models of migraine did not evaluate the sexual differences, and male mice or rats are normally tested [32,50].…”

Section: Discussionmentioning

confidence: 99%

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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“…TRPM8 is expressed mainly in a subpopulation of primary afferent neurons present in dorsal root and trigeminal ganglia, and in the nodose and geniculate ganglia of the peripheral nervous system. In these neurons, TRPM8 participates in the amplification of pain sensation after injury [6], suggesting that TRPM8 channel blockers could be effective for the treatment of chronic pain and migraine [7,8]. Furthermore, TRPM8 modulators have been investigated as therapeutics for the symptomatology of bladder pain syndromes, given their increased expression in patients suffering from these disorders [9].…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Pharmacological Characterization of a Novel TRPM8 Inhibitor Chemotype Identified by Small-Scale Preclinical Screening

Iraci

Ostacolo

Medina-Peris

et al. 2022

IJMS

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Transient receptor potential melastatin type 8 (TRPM8) is a target for the treatment of different physio-pathological processes. While TRPM8 antagonists are reported as potential drugs for pain, cancer, and inflammation, to date only a limited number of chemotypes have been investigated and thus a limited number of compounds have reached clinical trials. Hence there is high value in searching for new TRPM8 antagonistic to broaden clues to structure-activity relationships, improve pharmacological properties and explore underlying molecular mechanisms. To address this, the EDASA Scientific in-house molecular library has been screened in silico, leading to identifying twenty-one potentially antagonist compounds of TRPM8. Calcium fluorometric assays were used to validate the in-silico hypothesis and assess compound selectivity. Four compounds were identified as selective TRPM8 antagonists, of which two were dual-acting TRPM8/TRPV1 modulators. The most potent TRPM8 antagonists (BB 0322703 and BB 0322720) underwent molecular modelling studies to highlight key structural features responsible for drug–protein interaction. The two compounds were also investigated by patch-clamp assays, confirming low micromolar potencies. The most potent compound (BB 0322703, IC50 1.25 ± 0.26 μM) was then profiled in vivo in a cold allodinya model, showing pharmacological efficacy at 30 μM dose. The new chemotypes identified showed remarkable pharmacological properties paving the way to further investigations for drug discovery and pharmacological purposes.

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Androgenic TRPM8 activity drives sexual dimorphism in a murine model of chronic migraine

Cited by 3 publications

References 39 publications

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

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

In Vitro and In Vivo Pharmacological Characterization of a Novel TRPM8 Inhibitor Chemotype Identified by Small-Scale Preclinical Screening

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