Abstract
BackgroundStudies 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.MethodsWe 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.ResultsThe 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.ConclusionsThe 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.
Highlights
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)
Alterations in metabolite concentration Brainstem The glutamate concentration significantly increased from baseline to scan 1 after sildenafil compared to the corresponding change after placebo (P = 0.039) (Table 1, Fig. 5)
We found no interaction in the glutamate, lactate, NAA or total creatine concentrations in the brainstem or thalamus between participants who developed sildenafil- and/or CGRP-induced headaches as compared to participants who did not
Summary
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). 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. Human pharmacological migraine models have been used for the past two decades with great success to study migraine attack mechanisms using vasoactive drugs such as calcitonin gene-related peptide (CGRP) and sildenafil [1,2,3,4,5,6,7]. Methods for the study of pharmacologically induced biochemical effects on the brainstem glutamate levels have not been validated.
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