Any hypothesis regarding pain in primary headache disorders rests on the classic observations which describe painful sensations as a result of mechanical or electrical stimulation of large cerebral arteries, venous sinuses, and dural arteries, by Ray and Wolff (1). These pain-sensitive supratentorial structures are supplied by nerve fibres that arise in the trigeminal ganglion. The fibres and the cell bodies contain a number of messengers but calcitonin gene-related peptide (CGRP) is the one most frequently expressed (2). A role of the trigemino-cerebrovascular system in the transmission of nociceptive information to the central nervous system is thus a viable proposition. Antidromic or local mechanical stimulation of sensory nerve endings results in vasodilation via the release of vasoactive materials such as CGRP. The cell bodies are located in the trigeminal ganglion, they send sensory fibres to various cranial structures, and connect to the CNS via the trigeminal nerve. In primary headaches, there is a clear association between the headache and the release of CGRP, but not with any of the other neuronal messengers. The background and current status have recently been reviewed in the journal (3). Several primary headaches, such as migraine, cluster and chronic paroxysmal hemicrania, are associated with increased levels of CGRP in the jugular vein during pain (3). Furthermore, CGRP in the antecubital vein increases by 25–30% during nitroglycerin-induced migraine attacks and the increase in CGRP correlates markedly with the headache intensity (4). In the present issue of the journal Juhasz and colleagues (5) demonstrate that sumatriptan decreases the plasma CGRP concentration in the antecubital vein during migraine attacks elicited by nitroglycerin administration. This decrease was present only in those patients whose headache showed parallel clinical improvement. In those patients whose headache did not improve, the CGRP concentrations failed to show a decrease after the administration of nasal sumatriptan. Furthermore, plasma CGRP significantly correlated with headache scores after sumatriptan treatment. These results underline the close relationship of CGRP release and migraine headache (6).