Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia
Michael L Oshinsky, Angela L Murphy, Hugh Hekierski Jr, Marnie Cooper, Bruce J Simon, Michael L Oshinsky, Angela L Murphy, Hugh Hekierski Jr, Marnie Cooper, Bruce J Simon
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](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4025928/bin/nihms-580082-f0001.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4025928/bin/nihms-580082-f0002.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4025928/bin/nihms-580082-f0003.jpg)
Figure 4
Allodynic rats which received glyceryl…
Figure 4
Allodynic rats which received glyceryl trinitrate (GTN; 0.1mg/kg i.p.; n=5) had a greater…
Figure 5
Allodynic rats that received i.p.…
Figure 5
Allodynic rats that received i.p. glyceryl trinitrate (GTN; 0.1mg/kg; n=5) had a greater…
Figure 6
Levels of the inhibitor neurotransmitters…
Figure 6
Levels of the inhibitor neurotransmitters A) GABA, B) 5-HT C) norepinephrine, and D)…
- Episodic dural stimulation in awake rats: a model for recurrent headache.Oshinsky ML, Gomonchareonsiri S. Oshinsky ML, et al. Headache. 2007 Jul-Aug;47(7):1026-36. doi: 10.1111/j.1526-4610.2007.00871.x. Headache. 2007. PMID: 17635594 Free PMC article.
- Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response in a rat model.Liu TT, Morais A, Takizawa T, Mulder I, Simon BJ, Chen SP, Wang SJ, Ayata C, Yen JC. Liu TT, et al. J Headache Pain. 2022 Jan 21;23(1):12. doi: 10.1186/s10194-022-01384-1. J Headache Pain. 2022. PMID: 35062860 Free PMC article.
- Vagus nerve stimulation for primary headache disorders: An anatomical review to explain a clinical phenomenon.Henssen DJHA, Derks B, van Doorn M, Verhoogt N, Van Cappellen van Walsum AM, Staats P, Vissers K. Henssen DJHA, et al. Cephalalgia. 2019 Aug;39(9):1180-1194. doi: 10.1177/0333102419833076. Epub 2019 Feb 20. Cephalalgia. 2019. PMID: 30786731 Free PMC article.
- Vagus Nerve Stimulation and Headache.Yuan H, Silberstein SD. Yuan H, et al. Headache. 2017 Apr;57 Suppl 1:29-33. doi: 10.1111/head.12721. Epub 2015 Oct 16. Headache. 2017. PMID: 26473407 Review.
- TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice.Marone IM, De Logu F, Nassini R, De Carvalho Goncalves M, Benemei S, Ferreira J, Jain P, Li Puma S, Bunnett NW, Geppetti P, Materazzi S. Marone IM, et al. Brain. 2018 Aug 1;141(8):2312-2328. doi: 10.1093/brain/awy177. Brain. 2018. PMID: 29985973 Free PMC article.
- Non-invasive neuromodulation of the cervical vagus nerve in rare primary headaches.Villar-Martinez MD, Goadsby PJ. Villar-Martinez MD, et al. Front Pain Res (Lausanne). 2023 Mar 13;4:1062892. doi: 10.3389/fpain.2023.1062892. eCollection 2023. Front Pain Res (Lausanne). 2023. PMID: 36994091 Free PMC article. Review.
- Migraine and Neuromodulation: A Literature Review.Tiwari V, Agrawal S. Tiwari V, et al. Cureus. 2022 Nov 7;14(11):e31223. doi: 10.7759/cureus.31223. eCollection 2022 Nov. Cureus. 2022. PMID: 36505141 Free PMC article. Review.
- The Underlying Pathogenesis of Neurovascular Compression Syndromes: A Systematic Review.Szmyd B, Sołek J, Błaszczyk M, Jankowski J, Liberski PP, Jaskólski DJ, Wysiadecki G, Karuga FF, Gabryelska A, Sochal M, Tubbs RS, Radek M. Szmyd B, et al. Front Mol Neurosci. 2022 Jul 4;15:923089. doi: 10.3389/fnmol.2022.923089. eCollection 2022. Front Mol Neurosci. 2022. PMID: 35860499 Free PMC article.
- Therapeutic Devices for Motor Symptoms in Parkinson's Disease: Current Progress and a Systematic Review of Recent Randomized Controlled Trials.Fujikawa J, Morigaki R, Yamamoto N, Oda T, Nakanishi H, Izumi Y, Takagi Y. Fujikawa J, et al. Front Aging Neurosci. 2022 Mar 29;14:807909. doi: 10.3389/fnagi.2022.807909. eCollection 2022. Front Aging Neurosci. 2022. PMID: 35462692 Free PMC article. Review.
- Devices for Episodic Migraine: Past, Present, and Future.Moreno-Ajona D, Hoffmann J, Akerman S. Moreno-Ajona D, et al. Curr Pain Headache Rep. 2022 Mar;26(3):259-265. doi: 10.1007/s11916-022-01024-y. Epub 2022 Feb 11. Curr Pain Headache Rep. 2022. PMID: 35147856 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Dura Mater / drug effects
- Glutamic Acid / metabolism
- Headache / chemically induced
- Headache / metabolism
- Hyperalgesia / chemically induced
- Hyperalgesia / metabolism
- Hyperalgesia / therapy*
- Male
- Microdialysis
- Nitroglycerin
- Prostaglandins
- Rats
- Rats, Sprague-Dawley
- Treatment Outcome
- Trigeminal Neuralgia / chemically induced
- Trigeminal Neuralgia / metabolism
- Trigeminal Neuralgia / therapy*
- Vagus Nerve Stimulation / methods*
- gamma-Aminobutyric Acid / metabolism
- Prostaglandins
- Glutamic Acid
- gamma-Aminobutyric Acid
- Nitroglycerin
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
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![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4025928/bin/nihms-580082-f0004.jpg)
Figure 5
Allodynic rats that received i.p.…
Figure 5
Allodynic rats that received i.p. glyceryl trinitrate (GTN; 0.1mg/kg; n=5) had a greater…
Figure 6
Levels of the inhibitor neurotransmitters…
Figure 6
Levels of the inhibitor neurotransmitters A) GABA, B) 5-HT C) norepinephrine, and D)…
- Episodic dural stimulation in awake rats: a model for recurrent headache.Oshinsky ML, Gomonchareonsiri S. Oshinsky ML, et al. Headache. 2007 Jul-Aug;47(7):1026-36. doi: 10.1111/j.1526-4610.2007.00871.x. Headache. 2007. PMID: 17635594 Free PMC article.
- Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response in a rat model.Liu TT, Morais A, Takizawa T, Mulder I, Simon BJ, Chen SP, Wang SJ, Ayata C, Yen JC. Liu TT, et al. J Headache Pain. 2022 Jan 21;23(1):12. doi: 10.1186/s10194-022-01384-1. J Headache Pain. 2022. PMID: 35062860 Free PMC article.
- Vagus nerve stimulation for primary headache disorders: An anatomical review to explain a clinical phenomenon.Henssen DJHA, Derks B, van Doorn M, Verhoogt N, Van Cappellen van Walsum AM, Staats P, Vissers K. Henssen DJHA, et al. Cephalalgia. 2019 Aug;39(9):1180-1194. doi: 10.1177/0333102419833076. Epub 2019 Feb 20. Cephalalgia. 2019. PMID: 30786731 Free PMC article.
- Vagus Nerve Stimulation and Headache.Yuan H, Silberstein SD. Yuan H, et al. Headache. 2017 Apr;57 Suppl 1:29-33. doi: 10.1111/head.12721. Epub 2015 Oct 16. Headache. 2017. PMID: 26473407 Review.
- TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice.Marone IM, De Logu F, Nassini R, De Carvalho Goncalves M, Benemei S, Ferreira J, Jain P, Li Puma S, Bunnett NW, Geppetti P, Materazzi S. Marone IM, et al. Brain. 2018 Aug 1;141(8):2312-2328. doi: 10.1093/brain/awy177. Brain. 2018. PMID: 29985973 Free PMC article.
- Non-invasive neuromodulation of the cervical vagus nerve in rare primary headaches.Villar-Martinez MD, Goadsby PJ. Villar-Martinez MD, et al. Front Pain Res (Lausanne). 2023 Mar 13;4:1062892. doi: 10.3389/fpain.2023.1062892. eCollection 2023. Front Pain Res (Lausanne). 2023. PMID: 36994091 Free PMC article. Review.
- Migraine and Neuromodulation: A Literature Review.Tiwari V, Agrawal S. Tiwari V, et al. Cureus. 2022 Nov 7;14(11):e31223. doi: 10.7759/cureus.31223. eCollection 2022 Nov. Cureus. 2022. PMID: 36505141 Free PMC article. Review.
- The Underlying Pathogenesis of Neurovascular Compression Syndromes: A Systematic Review.Szmyd B, Sołek J, Błaszczyk M, Jankowski J, Liberski PP, Jaskólski DJ, Wysiadecki G, Karuga FF, Gabryelska A, Sochal M, Tubbs RS, Radek M. Szmyd B, et al. Front Mol Neurosci. 2022 Jul 4;15:923089. doi: 10.3389/fnmol.2022.923089. eCollection 2022. Front Mol Neurosci. 2022. PMID: 35860499 Free PMC article.
- Therapeutic Devices for Motor Symptoms in Parkinson's Disease: Current Progress and a Systematic Review of Recent Randomized Controlled Trials.Fujikawa J, Morigaki R, Yamamoto N, Oda T, Nakanishi H, Izumi Y, Takagi Y. Fujikawa J, et al. Front Aging Neurosci. 2022 Mar 29;14:807909. doi: 10.3389/fnagi.2022.807909. eCollection 2022. Front Aging Neurosci. 2022. PMID: 35462692 Free PMC article. Review.
- Devices for Episodic Migraine: Past, Present, and Future.Moreno-Ajona D, Hoffmann J, Akerman S. Moreno-Ajona D, et al. Curr Pain Headache Rep. 2022 Mar;26(3):259-265. doi: 10.1007/s11916-022-01024-y. Epub 2022 Feb 11. Curr Pain Headache Rep. 2022. PMID: 35147856 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Dura Mater / drug effects
- Glutamic Acid / metabolism
- Headache / chemically induced
- Headache / metabolism
- Hyperalgesia / chemically induced
- Hyperalgesia / metabolism
- Hyperalgesia / therapy*
- Male
- Microdialysis
- Nitroglycerin
- Prostaglandins
- Rats
- Rats, Sprague-Dawley
- Treatment Outcome
- Trigeminal Neuralgia / chemically induced
- Trigeminal Neuralgia / metabolism
- Trigeminal Neuralgia / therapy*
- Vagus Nerve Stimulation / methods*
- gamma-Aminobutyric Acid / metabolism
- Prostaglandins
- Glutamic Acid
- gamma-Aminobutyric Acid
- Nitroglycerin
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4025928/bin/nihms-580082-f0005.jpg)
Figure 6
Levels of the inhibitor neurotransmitters…
Figure 6
Levels of the inhibitor neurotransmitters A) GABA, B) 5-HT C) norepinephrine, and D)…
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4025928/bin/nihms-580082-f0006.jpg)
Source: PubMed