It is considered that the site of action of the abortive antimigraine compounds acting at serotonin, 5-HT1B/1D, receptors (triptans) is the trigeminovascular system. We tested whether there is a non-trigeminal site of action. The 5-HT1B/1D agonist, naratriptan, was microinjected into the ventrolateral periaqueductal gray (vlPAG), and activity in the trigeminal nucleus caudalis (TNC) was monitored. Recordings were made from 20 nociceptive neurons in the dorsal horn of the TNC that received convergent input from the dura mater and face. Responses of neurons to dural, facial cutaneous and corneal stimulation were studied before and after injection of naratriptan. Naratriptan decreased the excitability to electrical stimulation of the dura mater as the A-fiber response decreased by 24 ± 4.1% (p < 0.001) and the C-fiber response decreased by 42 ± 8.2% (p < 0.001). Spontaneous activity was decreased by 38 ± 7.5% (p < 0.001). After injection, the mechanical thresholds of the dura mater increased from (n = 14, p < 0.01). Responses to stimulation of the face and cornea were not altered by injection of naratriptan. These results suggest that 5-HT1B/1D receptor activation in the vlPAG activates descending pain-modulating pathways that inhibit dural, but not facial and corneal nociceptive input. These findings have implications for the understanding of the action of triptans in migraine and cluster headache, suggesting that brain loci other than the trigeminal nucleus may play a role in the clinical action of triptans. Ann Neurol 2004