Abstract
Migraine is a prevalent neurological disease that is characterized by unpredictable episodic attacks of intense head pain. The underlying pathology involves sensitization and activation of the trigeminal system. Although non-invasive vagus nerve stimulation (nVNS) is recommended for the treatment of migraine, the abortive mechanism of action is not well-understood. The goal of this study was to compare the ability of nVNS and sumatriptan to inhibit trigeminal activation in two animal models of episodic migraine and to investigate the receptor mechanism of action of nVNS. Nocifensive head withdrawal response was investigated in adult male Sprague Dawley rats using von Frey filaments. To induce trigeminal nociceptor sensitization, complete Freund's adjuvant was injected in the trapezius muscle and trigeminal neurons were activated by exposure to a pungent odor or injection of the nitric oxide donor sodium nitroprusside. Some animals received nVNS or sumatriptan as treatment. Some animals were injected intracisternally with antagonists of GABAA, 5-HT3 or 5-HT7 receptors prior to nVNS since these receptors are implicated in descending modulation. While unsensitized animals exposed to the pungent odor or nitric oxide alone did not exhibit enhanced mechanical nociception, sensitized animals with neck muscle inflammation displayed increased trigeminal nocifensive responses. The enhanced nociceptive response to both stimuli was attenuated by nVNS and sumatriptan. Administration of antagonists of GABAA, 5-HT3, and 5-HT7 receptors in the upper spinal cord suppressed the anti-nocifensive effect of nVNS. Our findings suggest that nVNS inhibits trigeminal activation to a similar degree as sumatriptan in episodic migraine models via involvement of GABAergic and serotonergic signaling to enhance central descending pain modulation.
Highlights
Migraine is a prevalent neurological disease characterized by unpredictable episodic attacks of severe head pain that is accompanied by autonomic symptoms including photophobia, phonophobia, and nausea [1]
The major finding from our study was that non-invasive vagus nerve stimulation (nVNS) was as effective as sumatriptan in inhibiting trigeminal nociception in two different rodent models of episodic migraine
NVNS and sumatriptan were both effective in inhibiting the increased level of trigeminal nociception mediated by California bay laurel (CBL) odor and nitric oxide in sensitized animals
Summary
Migraine is a prevalent neurological disease characterized by unpredictable episodic attacks of severe head pain that is accompanied by autonomic symptoms including photophobia, phonophobia, and nausea [1]. Migraine pathology involves sensitization and activation of the trigeminal system, which provides sensory innervation to much of the head and face including the meninges [5]. Non-invasive electrical stimulation of the vagus nerve has been reported to be beneficial in the treatment of migraine and cluster headache [6,7,8,9]. The pathological pain associated with migraine involves activation of trigeminal ganglion nerves, which provide sensory innervation of the head and face and relay nociceptive signals to the spinal trigeminal nucleus (STN) [10]. Effective to triptans, nVNS likely functions via different physiological and cellular mechanisms to modulate pain signaling in response to trigeminal nerve activation. The reported efficacy of nVNS may involve modulation of GABAergic and serotonergic signaling but this pathway has not been demonstrated in episodic migraine models
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