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J Headache Pain. 2018 Jun 18;19(1):44. 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.

Author information

1
Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark.
2
Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark.
3
Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and research, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark.
4
Neurobiology Research Unit, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
5
Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark. ashina@dadlnet.dk.

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:

Brainstem; CGRP; Glutamate; Glx; Lactate; MRS; Migraine; Sildenafil; Thalamus

PMID:
29916084
PMCID:
PMC6005999
DOI:
10.1186/s10194-018-0870-2
[Indexed for MEDLINE]
Free PMC Article

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