Unpredictable sound stress model causes migraine-like behaviors in mice with sexual dimorphism

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.