Blood-brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain.
In this study, we examined the effect of lambda-carrageenan-induced inflammatory pain on the functional and structural properties of the rat blood-brain barrier (BBB) over a 72-h time period. Systemic inflammation was induced by an intraplantar injection of 3% lambda-carrageenan into the right hind paw of female Sprague-Dawley rats. In situ brain perfusion and Western blot analyses were performed at 1, 3, 6, 12, 24, 48, and 72 h. In situ brain perfusion showed lambda-carrageenan significantly increased brain uptake of [(14)C]sucrose at 1, 3, 6, and 48 h (139 +/- 9%, 166 +/- 19%, 138 +/- 13%, and 146 +/- 7% compared with control, respectively). Capillary depletion analysis insured the increased brain uptake was due to increased BBB permeability and not vascular trapping. Western blot analyses for zonula occludens-1 (ZO-1) and occludin were performed on isolated cerebral microvessels. ZO-1 expression was significantly increased at 1, 3, and 6 h and returned to control expression levels by 12 h. Total occludin expression was significantly reduced at 1, 3, 6, 12, and 48 h. This investigation demonstrated that lambda-carrageenan-induced inflammatory pain elicits a biphasic increase in BBB permeability with the first phase occurring from 1-6 h and the second phase occuring at 48 h. Furthermore, changes in BBB function are correlated with altered tight junctional protein expression of occludin and ZO-1. Changes in the structure of tight junctions may have important clinical ramifications concerning central nervous system homeostasis and therapeutic drug delivery.
Huber
J D
JD
Department of Pharmacology, University of Arizona College of Medicine, Tucson 85724, USA.
Hau
V S
VS
Borg
L
L
Campos
C R
CR
Egleton
R D
RD
Davis
T P
TP
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002351:Carrageenan; D005260:Female; D051528:Guanylate Kinases; D015151:Immunoblotting; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D008565:Membrane Proteins / Q000032:analysis; D009703:Nucleoside-Phosphate Kinase / Q000032:analysis; D062793:Occludin; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010477:Perfusion; D010750:Phosphoproteins / Q000032:analysis; D011233:Precipitin Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000737:chemistry / Q000502:physiology*; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein
D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat; D010750:Phosphoproteins; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D002351:Carrageenan; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases