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

• Published in: British journal of pharmacology 2005-10, Vol.146 (4), p.576-584
• Main Authors: Hu, De‐En, Easton, Alexander S, Fraser, Paul A
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Blood–brain barrier; Brain Ischemia - chemically induced; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Capillaries - drug effects; Capillaries - metabolism; Capillaries - pathology; capillary permeability; Capillary Permeability - drug effects; Capillary Permeability - physiology; capsaicin; Capsaicin - administration & dosage; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; capsazepine; cerebral ischaemia; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Medical sciences; Microspheres; NK1; Pharmacology. Drug treatments; Piperidines - pharmacology; Rats; Rats, Wistar; Receptors, Neurokinin-1 - drug effects; Receptors, Neurokinin-1 - metabolism; Starch; Substance P - analogs & derivatives; Substance P - pharmacology; Tetrazoles - pharmacology; Time Factors; TRPV Cation Channels - drug effects; TRPV Cation Channels - metabolism; TRPV1
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706350

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. 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 EC50 −4.5±0.10. Substance P methyl ester gave a similar response (maximal 2.0±0.07, n=6, log EC50 −4.8±0.07), but the selective NK2 agonist, β‐Ala8‐NKA4–10 peptide, had no effect. Although CGRP decreased the permeability of venules (log EC50 10.3±0.11), its receptor antagonist CGRP8–37 had no effect on the response to capsaicin. 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 NK1 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 NK1. 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. 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. British Journal of Pharmacology (2005) 146, 576–584. doi:10.1038/sj.bjp.0706350