Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression

Abstract

Effects of inflammatory pain states on functional and molecular properties of the rat blood-brain barrier (BBB) were investigated. Inflammation was produced by subcutaneous injection of formalin, lambda-carrageenan, or complete Freund's adjuvant (CFA) into the right hind paw. In situ perfusion and Western blot analyses were performed to assess BBB integrity after inflammatory insult. In situ brain perfusion determined that peripheral inflammation significantly increased the uptake of sucrose into the cerebral hemispheres. Capillary depletion and cerebral blood flow analyses indicated the perturbations were due to increased paracellular permeability rather than vascular volume changes. Western blot analyses showed altered tight junctional protein expression during peripheral inflammation. Occludin significantly decreased in the lambda-carrageenan- and CFA-treated groups. Zonula occluden-1 expression was significantly increased in all pain models. Claudin-1 protein expression was present at the BBB and remained unchanged during inflammation. Actin expression was significantly increased in the lambda-carrageenan- and CFA-treated groups. We have shown that inflammatory-mediated pain alters both the functional and molecular properties of the BBB. Inflammatory-induced changes may significantly alter delivery of therapeutic agents to the brain, thus affecting dosing regimens during chronic pain.

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

“…This TJ disruption correlated with increased BBB paracellular permeability of [ 14 C]sucrose within the cerebral hemispheres. These data are in agreement with our previous findings that inflammatory hyperalgesia leads to functional changes in the BBB (Brooks et al, 2005;Hau et al, 2004;Huber et al, 2001Huber et al, , 2002aHuber et al, , b, 2006, and extends those findings to describe the earlier (i.e. 0-72 h) molecular alterations in TJ expression and co-localization, and changes in paracellular BBB integrity.…”

“…In addition to increased codeine transport into the brain, increased antinociceptive efficacy was noted. These changes in barrier function correlated with alterations in TJ proteins (Brooks et al, 2005;Hau et al, 2004;Huber et al, 2001Huber et al, , 2002a.…”

“…Our laboratory has described alterations in functional BBB integrity with several models of inflammatory pain (Brooks et al, 2005;Hau et al, 2004;Huber et al, 2001Huber et al, , 2002aHuber et al, , b, 2006. We have focused our studies on acute and chronic inflammatory pain, by examining the effects of λ-carrageenan (3%) and CFA, respectively, and through these studies we have discovered some common molecular mechanisms contributing to increased paracellular permeability at the BBB.…”

Antidepressant use and risk of central nervous system metastasis

“…These diseases may result from the change in permeability, or they may cause the change in permeability; for example, an ischemic stroke may increase the permeability of the BBB, but multiple sclerosis (MS) may be the result of the increase in permeability [86,99,107]. Hypoxia, inflammation, or other insults to the brain are associated with changes in BBB permeability [86,97,[108][109][110][111][112][113].…”

Iron supplement prevents lead-induced disruption of the blood–brain barrier during rat development

“…Furthermore, occludin is known to be much more highly expressed in brain endothelial cells than in endothelial cells of nonneural tissue (Hirase et al, 1997). Since occludin expression is down-regulated in various brain disorders accompanied by TJ disruption (Huber et al, 2001b;Davies, 2002), the expression level of occludin is important for TJ maintenance at the mature BBB. Therefore, analyzing the changes of the expression of occludin will provide deeper insight into the maintenance and disruption of the TJ properties at the BBB.…”