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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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: Multiple sclerosis (MS) is a chronic neurodegenerative, inflammatory and autoimmune disease characterised by the demyelination of the central nervous system. One of the main approaches to treating MS is the use of disease-modifying therapies (DMTs). Among the DMTs are interferons (IFNs), which are cytokines responsible for controlling the activity of the immune system, exerting immunomodulatory, antiviral, and antiproliferative activities. IFN-beta (IFN-β) is the first-choice drug used to treat relapsing-remitting MS. However, the administration of IFN-β causes numerous painful adverse effects, resulting in lower adherence to the treatment. Therefore, this study aimed to investigate the headache and flu-like pain symptoms observed after IFNβ injection in MS patients using a systematic review and meta-analysis of randomised controlled trials. The search of research databases identified 2370 articles. Nine articles were included (three involving IFNβ-1b and six involving IFNβ-1a). All studies included in the meta-analysis had a low risk of bias. Headache and flu-like pain symptoms frequency increased in MS patients treated with IFN-β. Thus, the adverse effects of headache and flu-like pain symptoms appear to be linked to IFN-β treatment in MS. The protocol of the study was registered in the Prospective International Registry of Systematic Reviews.