1. We describe the actions of GR43175, a 5-hydroxytryptamine1 (5-HT1)-like receptor agonist, on neurogenically-mediated plasma protein extravasation within an important pain-sensitive intracranial tissue, the dura mater. 2. GR43175 markedly attenuated extravasation of 125I-albumin from blood vessels within ipsilateral dura mater when administered to rats (100 micrograms kg-1) fifteen minutes before unilateral electrical trigeminal stimulation (1.2 mA, 5 Hz, 5 ms, 5 min); the ratio (stimulated/unstimulated sides) decreased from 1.81 to 1.23, P less than 0.005). 3. GR43175 (100 micrograms kg-1, i.v., rats; 30 micrograms kg-1, guinea-pigs) decreased the leakage of radiolabelled albumin from 163% to 119% (P less than 0.005, guinea-pig) or from 174 to 118% (P less than 0.05, rat) above vehicle-treated controls when injected ten minutes before systemic capsaicin treatment (0.5 or 1 mumol kg-1, i.v.). 4. GR43175 (30-300 micrograms kg-1) did not block plasma protein extravasation within extracranial tissues of rats and guinea-pigs innervated by the trigeminal nerve (conjunctiva, eyelid and lip). 5. The protein leakage which followed the i.v. administration of 5-HT (1 mumol kg-1) or neuropeptides which mediate neurogenic plasma extravasation, substance P (0.3 nmol kg-1 or 1 nmol kg-1) and neurokinin A (1 nmol kg-1), was not blocked by GR43175 (100, 300 micrograms kg-1) despite the presence of leakage in amounts equivalent to that following neurogenic stimulation. 6. GR43175 (100 micrograms kg-1) decreased bradykinin (10 mumol kg-1)-induced extravasation from 142 to 115% above vehicle-treated animals (P less than 0.05). 7. These results demonstrate an important action of GR43175 on neurogenic mechanisms in dural blood vessels. Since the ergot alkaloids possess a similar profile of drug activity, it is suggested that drugs useful in the treatment of acute vascular headaches may share a similar mechanism of action.