# Transcutaneous Auricular Vagus Nerve Stimulation Alleviates Headache Symptoms in Migraine Model Mice by the Locus Coeruleus/Noradrenergic System: An Experimental Study in a Mouse Model of Migraine

## TL;DR

This study shows that stimulating the vagus nerve in the ear can reduce headache symptoms in mice by activating a brain system related to norepinephrine.

## Contribution

The study identifies the locus coeruleus/noradrenergic system as a key mechanism for the pain-relieving effects of taVNS in migraine models.

## Key findings

- taVNS prolonged drinking time and reduced facial pain scores in migraine model mice.
- taVNS increased norepinephrine neuron count in the locus coeruleus and boosted norepinephrine release in Sp5C.
- taVNS upregulated α-2A adrenergic receptors in the spinal trigeminal nucleus caudalis.

## Abstract

Background/Objectives: Migraine is a complex neurological headache disorder, and transcutaneous auricular vagus nerve stimulation (taVNS) can effectively relieve headache symptoms, but its mechanism of effect is still unclear. This study aimed to explore the regulatory effects of taVNS on the locus coeruleus (LC) and the norepinephrine (NE) system in migraine mice. Methods: C57/BL6 mice were randomly assigned to four experimental groups: the control group, model group, taVNS group, and sham taVNS group. A migraine model was established by administration of nitroglycerin. Headache behaviors were assessed using the orofacial stimulation test (OST) and the mouse grimace scale (MGS). Immunofluorescence staining was conducted to evaluate the expression of NE neurons in the LC, while Western blotting was used to determine the expression levels of α-2A adrenergic receptors in the spinal trigeminal nucleus caudalis (Sp5C). Additionally, fiber-optic recording was employed to monitor the real-time dynamics of NE release in Sp5C. Results: After taVNS intervention, the drinking time of OST in the model mice was significantly prolonged(p < 0.05), and facial expression scores were reduced (p < 0.05). TaVNS increased the number of NE neurons in the LC (p < 0.05), promoted the release of NE in Sp5C (p < 0.05), and upregulated the expression of α-2A adrenergic receptors in Sp5C (p < 0.05). Conclusions: The analgesic effects of taVNS are related to the activation of the LC-NE system and the inhibition of the decrease in Sp5C in migraine mice.