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Am J Physiol Heart Circ Physiol (June 21, 2002). doi:10.1152/ajpheart.00027.2002
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Articles in PresS, published online ahead of print June 21, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00027.2002
Submitted on January 15, 2002
Accepted on June 12, 2002

Functional and Structural Analysis of Blood-Brain Barrier tight Junctions During a 72 Hr Exposure to [[lamda]]-Carrageenan Induced Inflammatory Pain

Jason D. Huber1*, Vincent S. Hau1, Lindsay Borg1, Chris R. Campos1, R D. Egleton1, and Thomas P. Davis1

1 Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA

* To whom correspondence should be addressed. E-mail: huberj{at}u.arizona.edu.

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 hr 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 hr. In situ brain perfusion showed {lambda}-carrageenan significantly increased brain uptake of [14C] sucrose at 1, 3, 6, and 48 hr [139 ± 9, 166 ± 19, 138 ± 13, and 146 ± 7% compared to control, respectively]. Capillary depletion analysis insured the increased brain uptake was due to increased paracellular permeability at the BBB 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 hr and returned to control expression levels by 12 hr. Total occludin expression was significantly reduced at 1, 3, 6, 12, and 48 hr. This investigation demonstrated {lambda}-carrageenan induced inflammatory pain elicits a biphasic increase in BBB paracellular permeability with the first phase occurring from 1-6 hr and the second at 48 hr. 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.




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