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.