TRPV1 activation results in disruption of the blood-brain barrier in the rat

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 2.1±0.12 × 10 ^-6 cm s ^-1 (mean±s.e.m.) with log EC ₅₀4.5±0.10. Substance P methyl ester gave a similar response (maximal 2.0±0.07, n=6, log EC ₅₀ -4.8±0.07), but the selective NK ₂ agonist, β-Ala ₈-NKA _4-10 peptide, had no effect. Although CGRP decreased the permeability of venules (log EC ₅₀ 10.3±0.11), 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 μM), from 1.78±0.15 to 0.63±0.10 (n=4). The NK ₁ receptor antagonists GR205171 (100 μM) and SDZ NKT 376 (1 mM) also reduced the response to capsaicin (from 1.75±0.14 to 0.46±0.08; n=6, and from 1.85±0.13 to 0.48±0.05; n=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 μm than those less than 15 μm. Capsazepine given intraperitoneally during ischaemia reduced the permeability increase in small venules from 5.9±0.3 to 2.4±0.1, and from 11.4±0.8 to 5.1±0.9 in large venules. 5. In conclusion, the TRPV1 receptor is active in the brain microvasculature and has its permeability-increasing effect via substance P. It also plays a role in the immediate blood-brain barrier disruption following ischaemia- reperfusion.