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

Viero, Fernanda Tibolla; Rodrigues, Patrícia; Frare, Julia Maria; Silva, Náthaly da; Ferreira, Marcella de Amorim; Silva, Ana da; Pereira, Gabriele Cheiran; Ferreira, Juliano; Pillat, Micheli Mainardi; Bochi, Guilherme Vargas; Nassini, Romina; Geppetti, Pierangelo; Trevisan, Gabriela

doi:10.22541/au.164873348.84448275/v1

Cited by 2 publications

(2 citation statements)

References 52 publications

(102 reference statements)

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“…Further, only females exhibited anxiety and increased levels of IL-6. Female-specific increases in IL-6 levels have been observed in mouse models of TMD and stress ( 91, 92 ), suggesting it may represent a marker of sexual dimorphism. In previous work, we also found that the joint effects of COMT inhibition and stress on sexual dimorphism in pain and depressive behavior were linked to female-specific changes in the expression of brain derived neurotrophic factor (BDNF) in the spinal cord and hippocampus ( 93 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Mouse Model of Chronic Primary Pain Conditions that Integrates Clinically Relevant Genetic and Environmental Factors

Wang

Kim

Klein

et al. 2022

Preprint

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Chronic primary pain conditions (CPPCs) affect over 100 million people, predominantly women. Yet, they remain ineffectively treated due, in large part, to lack of valid animal models with translational relevance. Here, we characterized a novel mouse model of CPPCs that integrated clinically-relevant genetic (catechol-o-methyltransferase; COMT knockdown) and environmental (stress and minor injury) factors. Compared to wildtype mice, COMT+/- mice undergoing the repeated swim stress and molar extraction surgery intervention exhibited pronounced multi-site body pain and depressive-like behavior lasting more than 3 months. The COMT+/- mice undergoing the intervention also exhibited enhanced activity of primary afferent DRG nociceptors innervating hindpaw and back sites and increased plasma levels of norepinephrine and the pro-inflammatory cytokines IL-6 and IL-17A. Notably, the pain and depressive-like behavior was of greater magnitude and longer duration (lasting at least 12 months) in females compared to males. Further, increases in anxiety-like behavior and IL-6 levels were female-specific. Intervention-induced body pain and nociception in COMT+/- mice was blocked by a beta-3 adrenergic antagonist, demonstrating predictive validity. Finally, the effect of COMT genotype x stress interactions on pain and IL-6 and IL-17A levels was observed in our clinical CPPC case-control cohort, demonstrating construct validity. Thus, our novel mouse model reliably recapitulates clinically- and biologically-relevant features of CPPCs and can be further implemented to test underlying mechanisms and discover new therapeutics.

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Section: Discussionmentioning

confidence: 99%

A Novel Mouse Model of Chronic Primary Pain Conditions that Integrates Clinically Relevant Genetic and Environmental Factors

Wang

Kim

Klein

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Also, the International Society for Advancement of Cytometry Marylou Ingram Scholar (ISAC). This paper was posted on a preprint server Authorea https://doi.org/10.22541/au.164873348.84448275/v1 ( Viero et al, 2022b ).…”

mentioning

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

Cited by 2 publications

References 52 publications

A Novel Mouse Model of Chronic Primary Pain Conditions that Integrates Clinically Relevant Genetic and Environmental Factors

A Novel Mouse Model of Chronic Primary Pain Conditions that Integrates Clinically Relevant Genetic and Environmental Factors

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

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