Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients

Nitroglycerine is known to induce a headache attack in cluster headache patients, which is indistinguishable from a spontaneous attack. It has recently been suggested that a release of calcitonin gene-related peptide (CGRP) from peripheral terminals of trigeminal nociceptive neurons, which supply cephalic blood vessels, underlies symptoms of cluster headache. The aim of this study was to investigate whether the provocative action of nitroglycerine in cluster headache is due, at least in part, to activation of the trigeminovascular system. Nineteen subjects suffering from episodic cluster headache participated in the study. Eleven of them were in an active period whilst the others were in remission at the time of the study. CGRP-like immunoreactivity (CGRP-LI) was measured in blood samples from the extracerebral circulation before and after the sublingual administration of nitroglycerine. Baseline CGRP-LI plasma levels were higher (P < 0.05) in the patients who were in an active period. Only in these patients did nitroglycerine induce an attack, which was preceded by a latent period with a mean duration of 27+/-3 min. When compared with the baseline, a significant (P<0.01) increase in plasma CGRP-LI was detected at the peak of the provoked attack; no such increase was detected during the latent period, or at the onset of the attack. The results of this study suggests that the provocative action of nitroglycerine in cluster headache is due, at least in part, to activation of the trigeminovacular system. This mechanism seems to be slow and unrelated to the well-known rapidly occurring vasodilator effects of the drug. Finally, activation of the trigeminovascular system only occurs in those patients already in an active cluster headache period who also have high basal CGRP-LI plasma levels. This suggests that a hyperactivity of trigeminal nociceptive fibres could make the trigeminovascular system of these patients sensitive to the triggering action of nitroglycerine.