INTRODUCTION
Migraine is a pain disorder characterized by atypical neurological symptoms that occur in the absence of tissue injury. It is classified as a type of primary headache, which represents one of the highest causes of disability worldwide. Migraine has a major female prevalence under 50 years and has a challenging treatment [23]. Also, it has been showed that migraine may be related to psychiatric disorders, including anxiety [27]. The migraine attacks are elicited by a variety of agents, such as stress induction and others [30]. Stress is the most common trigger reported in migraine patients, also it can raise the duration of the crisis and the induction of chronic migraine [30,53].
Thus, different stress models have been used to induce migraine-like behaviors (periorbital/hind paw mechanical allodynia, grimacing pain behavior, and anxiety-related symptoms) in mice to better study the mechanisms involved in this painful disease. These previous studies used acute or chronic stress caused by repetitive restrain stress paradigm, social defeat, chronic variable, and early life stress [8,20]. Besides, sound stress seems to be a relevant mediator of headache induction in patients [26]. Previous studies using an unpredictable sound stress model have observed the development of plantar nociception (hind paw allodynia and chemical hyperalgesia) in male rats [32]. Nevertheless, the development of migraine-like behaviors using this stress model has not been evaluated yet.
The relationship among calcitonin gene-related peptide (CGRP) signaling and stress-mediated migraine-like behaviors has been investigated in only one preclinical study [8]. CGRP has been implicated in the pathology of migraine for several decades [31]. Recent clinical studies have further confirmed a protagonist of CGRP in migraine due the use of inhibitors of CGRP signaling [24]. CGRP antagonist (olcegepant, BIBN4096BS) was effective to reduce periorbital allodynia in different models of migraine-like pain [16]. Besides, CGRP injection to the trigeminovascular system causes periorbital mechanical allodynia and anxiety like-behavior, that was prolonged in female rats [5].
CGRP may lead to the release of pro-inflammatory cytokines [44], and the levels of interleukine-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were increased in the plasm of migraine patients [14]. In fact, the application of IL-6 in dura mater and cisterna magna causes both periorbital and hind paw cutaneous hypersensitivity [9]. Also, TNF-α injection was able to sensitize the dural meningeal nociceptors [57]. Previously, skeletal muscle hyperalgesia caused by unpredictable sound stress model was reduced by the treatment with antisense targeting the IL-6 or TNF-α receptors [17].
Thus, the mechanisms involved in stress induction of migraine-related pain need to be studied to reach a better treatment for this painful disease. Here, we initially characterized the periorbital/hind paw mechanical allodynia, grimacing pain behavior, and anxiety-related symptoms after the induction of unpredictable sound stress in male and female mice and the effect of a CGRP antagonist. Second, we detected the plasmatic levels of pro-inflammatory cytokines and CGRP.