1 We have examined the role of TRPV1 activation in disrupting the blood-brain barrier by measuring the permeability of single pial venular capillaries in anaesthetized rats. 2 Capsaicin application to the brain surface resulted in increased permeability, maximal 2.170.12 Â 10 À6 cm s À1 (mean7s.e.m.) with log EC 50 À4.570.10. Substance P methyl ester gave a similar response (maximal 2.070.07, n ¼ 6, log EC 50 À4.870.07), but the selective NK 2 agonist, b-Ala 8 -NKA 4-10 peptide, had no effect. Although CGRP decreased the permeability of venules (log EC 50 10.370.11), its receptor antagonist CGRP 8-37 had no effect on the response to capsaicin. 3 The TRPV1 antagonist capsazepine (1 mM) reduced the response to capsaicin (100 mM), from 1.7870.15 to 0.6370.10 (n ¼ 4). The NK 1 receptor antagonists GR205171 (100 mM) and SDZ NKT 376 (1 mM) also reduced the response to capsaicin (from 1.7570.14 to 0.4670.08; n ¼ 6, and from 1.8570.13 to 0.4870.05; n ¼ 5, respectively), indicating that capsaicin acts via TRPV1 in series with NK 1 . 4 Starch microspheres were used to produce transient focal ischaemia. Permeability was increased on reperfusion to a greater extent and more rapidly in vessels with diameter greater than 40 mm than those less than 15 mm. Capsazepine given intraperitoneally during ischaemia reduced the permeability increase in small venules from 5.970.3 to 2.470.1, and from 11.470.8 to 5.170.9 in large venules. 5 In conclusion, the TRPV1 receptor is active in the brain microvasculature and has its permeabilityincreasing effect via substance P. It also plays a role in the immediate blood-brain barrier disruption following ischaemia-reperfusion.