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Introduction: Chronic headache conditions are characterized by persistent sensitization of the trigeminal system, which involves dysfunction of descending pain modulation. We previously reported that noninvasive vagus nerve stimulation (nVNS) inhibits trigeminal nociception in models of episodic migraine through a mechanism involving enhanced serotonergic and GABAergic descending pain signaling., Objectives: The analgesic effectiveness of nVNS and morphine were investigated in an animal model of chronic headache mediated by the combination of the 3 migraine risk factors of neck muscle tension, paradoxical sleep deprivation, and pungent odors., Methods: Sprague-Dawley rats were injected with complete Freund's adjuvant in the trapezius and sleep deprived for 1 night to promote trigeminal sensitization. After 7 days, animals were exposed to a pungent odor, and mechanical nocifensive head withdrawal responses were determined using von Frey filaments. Beginning on day 3 after odor exposure, animals were treated daily with either nVNS or morphine for 7 days., Results: Exposure of animals sensitized by neck inflammation and sleep deprivation to a pungent odor resulted in a prolonged state of trigeminal nociception. Daily administration of nVNS or morphine significantly repressed the nocifensive response; however, cessation resulted in a return to heightened pretreatment nocifensive levels., Conclusions: The combination of reported migraine risk factors promotes a state of sustained trigeminal hypersensitivity characteristic of chronic headache. Daily nVNS was similarly effective as morphine in inhibiting nociception and may represent a safer, opioid-sparing therapeutic option for other chronic pain disorders involving sensitization of the trigeminal system by promoting descending pain modulation., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Introduction: Although neck muscle tension is considered a risk factor for migraine, pungent odors can act as a trigger to initiate an attack in sensitized individuals. Although noninvasive vagus nerve stimulation (nVNS) is now an approved treatment for chronic migraine, how it functions to inhibit trigeminal nociception in an episodic migraine model is not known., Objectives: The objectives of this study were to determine if nVNS could inhibit trigeminal nociception in a novel model of episodic migraine and investigate changes in the expression of proteins implicated in peripheral and central sensitization., Methods: Sprague-Dawley male rats were injected with an inflammatory agent in the trapezius muscle before exposure to pungent volatile compounds, which was used to initiate trigeminal nociceptor activation. The vagus nerve was stimulated transdermally by a 1-ms pulse of 5 kHz sine waves, repeated at 25 Hz for 2 minutes. Nocifensive head withdrawal response to von Frey filaments was determined and immunoreactive protein levels in the spinal cord and trigeminal ganglion (TG) were investigated., Results: Exposure to the pungent odor significantly increased the number of nocifensive withdrawals in response to mechanical stimulation of sensitized TG neurons mediated by neck muscle inflammation. Noninvasive vagus nerve stimulation inhibited nociception and repressed elevated levels of P-ERK in TG, Iba1 in microglia, and GFAP in astrocytes from sensitized animals exposed to the pungent odor., Conclusion: Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.