Effects of sildenafil and calcitonin gene-related peptide on brainstem glutamate levels: a pharmacological proton magnetic resonance spectroscopy study at 3.0 T

Samaira Younis; Anders Hougaard; Casper Emil Christensen; Mark Bitsch Vestergaard; Esben Thade Petersen; Olaf Bjarne Paulson; Henrik Bo Wiberg Larsson; Messoud Ashina

doi:10.1186/s10194-018-0870-2

Effects of sildenafil and calcitonin gene-related peptide on brainstem glutamate levels: a pharmacological proton magnetic resonance spectroscopy study at 3.0 T

Samaira Younis, Anders Hougaard, Casper Emil Christensen, Mark Bitsch Vestergaard, Esben Thade Petersen, Olaf Bjarne Paulson, Henrik Bo Wiberg Larsson, Messoud Ashina

Department of Clinical Medicine

3 Citations (Scopus)

38 Downloads (Pure)

Abstract

BACKGROUND: Studies involving human pharmacological migraine models have predominantly focused on the vasoactive effects of headache-inducing drugs, including sildenafil and calcitonin gene-related peptide (CGRP). However, the role of possible glutamate level changes in the brainstem and thalamus is of emerging interest in the field of migraine research bringing forth the need for a novel, validated method to study the biochemical effects in these areas.

METHODS: We applied an optimized in vivo human pharmacological proton (1H) magnetic resonance spectroscopy (MRS) protocol (PRESS, repetition time 3000 ms, echo time 37.6-38.3 ms) at 3.0 T in combination with sildenafil and CGRP in a double-blind, placebo-controlled, randomized, double-dummy, three-way cross-over design. Seventeen healthy participants were scanned with the 1H-MRS protocol at baseline and twice (at 40 min and 140 min) after drug administration to investigate the sildenafil- and CGRP-induced glutamate changes in both brainstem and thalamus.

RESULTS: The glutamate levels increased transiently in the brainstem at 40-70 min after sildenafil administration compared to placebo (5.6%, P = 0.039). We found no sildenafil-induced glutamate changes in the thalamus, and no CGRP-induced glutamate changes in the brainstem or thalamus compared to placebo. Both sildenafil and CGRP induced headache in 53%-62% of participants. We found no interaction in the glutamate levels in the brainstem or thalamus between participants who developed sildenafil and/or CGRP-induced headache as compared to participants who did not.

CONCLUSIONS: The transient sildenafil-induced glutamate change in the brainstem possibly reflects increased excitability of the brainstem neurons. CGRP did not induce brainstem or thalamic glutamate changes, suggesting that it rather exerts its headache-inducing effects on the peripheral trigeminal pain pathways.

Original language	English
Article number	44
Journal	The Journal of Headache and Pain
Volume	19
Number of pages	11
ISSN	1129-2369
DOIs	https://doi.org/10.1186/s10194-018-0870-2
Publication status	Published - 1 Dec 2018

Keywords

Adolescent
Adult
Brain Stem/drug effects
Calcitonin Gene-Related Peptide/pharmacology
Double-Blind Method
Female
Glutamic Acid/metabolism
Humans
Male
Middle Aged
Neurons/drug effects
Proton Magnetic Resonance Spectroscopy
Sildenafil Citrate/pharmacology
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Younis, S., Hougaard, A., Christensen, C. E., Vestergaard, M. B., Petersen, E. T., Paulson, O. B., Larsson, H. B. W., & Ashina, M. (2018). Effects of sildenafil and calcitonin gene-related peptide on brainstem glutamate levels: a pharmacological proton magnetic resonance spectroscopy study at 3.0 T. The Journal of Headache and Pain, 19, Article 44. https://doi.org/10.1186/s10194-018-0870-2

Effects of sildenafil and calcitonin gene-related peptide on brainstem glutamate levels: a pharmacological proton magnetic resonance spectroscopy study at 3.0 T. / Younis, Samaira; Hougaard, Anders; Christensen, Casper Emil et al.
In: The Journal of Headache and Pain, Vol. 19, 44, 01.12.2018.

Research output: Contribution to journal › Journal article › Research › peer-review

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abstract = "BACKGROUND: Studies involving human pharmacological migraine models have predominantly focused on the vasoactive effects of headache-inducing drugs, including sildenafil and calcitonin gene-related peptide (CGRP). However, the role of possible glutamate level changes in the brainstem and thalamus is of emerging interest in the field of migraine research bringing forth the need for a novel, validated method to study the biochemical effects in these areas.METHODS: We applied an optimized in vivo human pharmacological proton (1H) magnetic resonance spectroscopy (MRS) protocol (PRESS, repetition time 3000 ms, echo time 37.6-38.3 ms) at 3.0 T in combination with sildenafil and CGRP in a double-blind, placebo-controlled, randomized, double-dummy, three-way cross-over design. Seventeen healthy participants were scanned with the 1H-MRS protocol at baseline and twice (at 40 min and 140 min) after drug administration to investigate the sildenafil- and CGRP-induced glutamate changes in both brainstem and thalamus.RESULTS: The glutamate levels increased transiently in the brainstem at 40-70 min after sildenafil administration compared to placebo (5.6%, P = 0.039). We found no sildenafil-induced glutamate changes in the thalamus, and no CGRP-induced glutamate changes in the brainstem or thalamus compared to placebo. Both sildenafil and CGRP induced headache in 53%-62% of participants. We found no interaction in the glutamate levels in the brainstem or thalamus between participants who developed sildenafil and/or CGRP-induced headache as compared to participants who did not.CONCLUSIONS: The transient sildenafil-induced glutamate change in the brainstem possibly reflects increased excitability of the brainstem neurons. CGRP did not induce brainstem or thalamic glutamate changes, suggesting that it rather exerts its headache-inducing effects on the peripheral trigeminal pain pathways.",

keywords = "Adolescent, Adult, Brain Stem/drug effects, Calcitonin Gene-Related Peptide/pharmacology, Double-Blind Method, Female, Glutamic Acid/metabolism, Humans, Male, Middle Aged, Neurons/drug effects, Proton Magnetic Resonance Spectroscopy, Sildenafil Citrate/pharmacology, Young Adult",

author = "Samaira Younis and Anders Hougaard and Christensen, {Casper Emil} and Vestergaard, {Mark Bitsch} and Petersen, {Esben Thade} and Paulson, {Olaf Bjarne} and Larsson, {Henrik Bo Wiberg} and Messoud Ashina",

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T1 - Effects of sildenafil and calcitonin gene-related peptide on brainstem glutamate levels

T2 - a pharmacological proton magnetic resonance spectroscopy study at 3.0 T

AU - Younis, Samaira

AU - Hougaard, Anders

AU - Christensen, Casper Emil

AU - Vestergaard, Mark Bitsch

AU - Petersen, Esben Thade

AU - Paulson, Olaf Bjarne

AU - Larsson, Henrik Bo Wiberg

AU - Ashina, Messoud

PY - 2018/12/1

Y1 - 2018/12/1

N2 - BACKGROUND: Studies involving human pharmacological migraine models have predominantly focused on the vasoactive effects of headache-inducing drugs, including sildenafil and calcitonin gene-related peptide (CGRP). However, the role of possible glutamate level changes in the brainstem and thalamus is of emerging interest in the field of migraine research bringing forth the need for a novel, validated method to study the biochemical effects in these areas.METHODS: We applied an optimized in vivo human pharmacological proton (1H) magnetic resonance spectroscopy (MRS) protocol (PRESS, repetition time 3000 ms, echo time 37.6-38.3 ms) at 3.0 T in combination with sildenafil and CGRP in a double-blind, placebo-controlled, randomized, double-dummy, three-way cross-over design. Seventeen healthy participants were scanned with the 1H-MRS protocol at baseline and twice (at 40 min and 140 min) after drug administration to investigate the sildenafil- and CGRP-induced glutamate changes in both brainstem and thalamus.RESULTS: The glutamate levels increased transiently in the brainstem at 40-70 min after sildenafil administration compared to placebo (5.6%, P = 0.039). We found no sildenafil-induced glutamate changes in the thalamus, and no CGRP-induced glutamate changes in the brainstem or thalamus compared to placebo. Both sildenafil and CGRP induced headache in 53%-62% of participants. We found no interaction in the glutamate levels in the brainstem or thalamus between participants who developed sildenafil and/or CGRP-induced headache as compared to participants who did not.CONCLUSIONS: The transient sildenafil-induced glutamate change in the brainstem possibly reflects increased excitability of the brainstem neurons. CGRP did not induce brainstem or thalamic glutamate changes, suggesting that it rather exerts its headache-inducing effects on the peripheral trigeminal pain pathways.

AB - BACKGROUND: Studies involving human pharmacological migraine models have predominantly focused on the vasoactive effects of headache-inducing drugs, including sildenafil and calcitonin gene-related peptide (CGRP). However, the role of possible glutamate level changes in the brainstem and thalamus is of emerging interest in the field of migraine research bringing forth the need for a novel, validated method to study the biochemical effects in these areas.METHODS: We applied an optimized in vivo human pharmacological proton (1H) magnetic resonance spectroscopy (MRS) protocol (PRESS, repetition time 3000 ms, echo time 37.6-38.3 ms) at 3.0 T in combination with sildenafil and CGRP in a double-blind, placebo-controlled, randomized, double-dummy, three-way cross-over design. Seventeen healthy participants were scanned with the 1H-MRS protocol at baseline and twice (at 40 min and 140 min) after drug administration to investigate the sildenafil- and CGRP-induced glutamate changes in both brainstem and thalamus.RESULTS: The glutamate levels increased transiently in the brainstem at 40-70 min after sildenafil administration compared to placebo (5.6%, P = 0.039). We found no sildenafil-induced glutamate changes in the thalamus, and no CGRP-induced glutamate changes in the brainstem or thalamus compared to placebo. Both sildenafil and CGRP induced headache in 53%-62% of participants. We found no interaction in the glutamate levels in the brainstem or thalamus between participants who developed sildenafil and/or CGRP-induced headache as compared to participants who did not.CONCLUSIONS: The transient sildenafil-induced glutamate change in the brainstem possibly reflects increased excitability of the brainstem neurons. CGRP did not induce brainstem or thalamic glutamate changes, suggesting that it rather exerts its headache-inducing effects on the peripheral trigeminal pain pathways.

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KW - Adult

KW - Brain Stem/drug effects

KW - Calcitonin Gene-Related Peptide/pharmacology

KW - Double-Blind Method

KW - Female

KW - Glutamic Acid/metabolism

KW - Humans

KW - Male

KW - Middle Aged

KW - Neurons/drug effects

KW - Proton Magnetic Resonance Spectroscopy

KW - Sildenafil Citrate/pharmacology

KW - Young Adult

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DO - 10.1186/s10194-018-0870-2

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C2 - 29916084

SN - 1129-2369

VL - 19

JO - The Journal of Headache and Pain

JF - The Journal of Headache and Pain

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