1. The ability of an NK1 receptor antagonist, RPR 100893, and its enantiomer, RPR 103253 to block neurogenic plasma protein extravasation in guinea-pig dura mater and conjunctiva was assessed following 125I-labelled bovine serum albumin ([125I]-BSA, 50 muCi kg-1, i.v.) and unilateral electrical stimulation of the trigeminal ganglion (0.6 mA, 5 ms, 5 Hz, 5 min) or capsaicin administration (150 micrograms kg-1, i.v.). 2. When administered p.o. 60 min prior to electrical stimulation, RPR 100893 (> or = 0.1 microgram kg-1) decreased plasma protein extravasation in dura mater in a dose-dependent manner, whereas the enantiomer (10 or 100 micrograms kg-1, p.o.) was inactive. 3. When given i.v. 30 min prior to electrical stimulation, RPR 100893 (> or = 0.5 ng kg-1) significantly inhibited plasma protein extravasation in the dura mater evoked by electrical stimulation in a dose-dependent manner. 4. RPR 100893 (100 micrograms kg-1, p.o.) also reduced the leakage when given 45 min before the guinea-pigs were killed and 10, 40 and 80 min after electrical trigeminal stimulation. 5. RPR 100893 given p.o. dose-dependently inhibited capsaicin-induced plasma protein extravasation with ID50S of 7.4 micrograms kg-1 and 82 micrograms kg-1 for dura mater and conjunctiva, respectively. 6. These results are consistent with the contention that NK1 receptors mediate neurogenic plasma protein leakage following trigeminal stimulation, and suggest that NK1 receptor antagonists of the perhydroisoindolone series may be useful for treating migraine and cluster headaches.