Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia

Abstract

Implanted vagus nerve stimulation (VNS) has been used to treat seizures and depression. In this study, we explored the mechanism of action of noninvasive vagus nerve stimulation (nVNS) for the treatment of trigeminal allodynia. Rats were repeatedly infused with inflammatory mediators directly onto the dura, which led to chronic trigeminal allodynia. Administration of nVNS for 2 minutes decreased periorbital sensitivity in rats with periorbital trigeminal allodynia for up to 3.5 hours after stimulation. Using microdialysis, we quantified levels of extracellular neurotransmitters in the trigeminal nucleus caudalis (TNC). Allodynic rats showed a 7.7±0.9-fold increase in extracellular glutamate in the TNC after i.p. administration of the chemical headache trigger glyceryl trinitrate (GTN; 0.1 mg/kg). Allodynic rats that received nVNS had only a 2.3±0.4-fold increase in extracellular glutamate after GTN, similar to the response in control naive rats. When nVNS was delayed until 120 minutes after GTN treatment, the high levels of glutamate in the TNC were reversed after nVNS. The nVNS stimulation parameters used in this study did not produce significant changes in blood pressure or heart rate. These data suggest that nVNS may be used to treat trigeminal allodynia.

Keywords: Chronic headache; Glutamate; Migraine; Vagus nerve.

Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1

A) An Elizabethan collar with two silver coated electrodes (0.8cm diameter) was placed on conscious naive and allodynic rats. The electrodes were connected to an amplifier that produced 1ms pulse of 5kHz sine waves, repeated at 25Hz. The electrodes were positioned on the skin of the rat, lateral to the rat’s trachea. Figure 1B) Although in the experiments in this study vagus nerve stimulation was achieved through stimulation of the shaved skin on the neck over the vagus nerve, we have included a diagram of the anatomy of the neck of the rat to illustrate the placement electrodes with respect to the vagus nerve. This diagram is a cutaway of the rat’s neck that shows the trachea (white), carotid artery (red) and vagus nerve (yellow) in relation to the placement of the electrodes (blue).

Figure 2

A) Blood pressure was monitored via femoral artery catheterization. Anesthetized rats were monitored for an hour then given non-invasive vagus nerve stimulation for 2 minutes, and monitored for 45min (n=4). We found that nVNS did not cause any significant change in blood pressure (97.17±0.57 mmHg). Figure 2B) Heart rate was monitored via femoral artery catheterization. Anesthetized rats were monitored for an hour then given non-invasive vagus nerve stimulation for 2 minutes, and monitored for 45min (n=4). We found that nVNS using our parameters did not cause any significant change in heart rate (143.32±8.09 beats/min).

Figure 3

Using electrodes attached to an Elizabethan collar, conscious naive and allodynic rats received nVNS. Periorbital thresholds were compared to pre-stimulation levels. Following nVNS, allodynic rats significantly increased their thresholds significantly above baseline relative to control animals (Repeated measure ANOVA p

Figure 4

Allodynic rats which received glyceryl trinitrate (GTN; 0.1mg/kg i.p.; n=5) had a greater than 7 fold increase in extracellular glutamate in the trigeminal nucleus caudalis (TNC). Allodynic rats that were treated with 2 minutes of nVNS at the same time as GTN injection exhibited only a 2.5 fold increase in extracellular glutamate in the TNC (n=5), similar to the GTN response in naive rats (n=5; *p

Figure 5

Allodynic rats that received i.p. glyceryl trinitrate (GTN; 0.1mg/kg; n=5) had a greater than 7 fold increase in extracellular glutamate in the trigeminal nucleus caudalis (TNC). Allodynic rats that were treated with 2 minutes of nVNS 120 minutes after the GTN injection (n=5) reversed the increase in glutamate noted in the untreated rats. (one-way ANOVA *p

Figure 6

Levels of the inhibitor neurotransmitters A) GABA, B) 5-HT C) norepinephrine, and D) glycine in the trigeminal nucleus caudalis (TNC) of allodynic rats that received i.p. glyceryl trinitrate (GTN; 0.1mg/kg) after baseline and 2 min of nVNS 120 minutes later (n=5). There was no significant change in the levels of GABA, 5-HT, norepinephrine and glycine.