Central regulation of Blood Brain Barrier integrity during hyperalgesia

Abstract

The blood-brain barrier (BBB) is located at the level of the cerebral microcapillaries, and functions to maintain environmental homeostasis by allowing the neurons access to the required nutrients and enabling the exchange of metabolic waste. BBB dysfunction has been observed in a number of pathophysiologic statres including peripheral inflammatory pain (Huber et al., 2001b). Using the lamda-carrageenan inflammatory pain (CIP) model, we observed alterations in the tight junction (TJ) proteins paralleled by an increase in BBB permeability to [14C] sucrose. The mechanisms by which these perturbations occurred remain to be elucidated. In the current study, we investigate the central mechanism for the BBB perturbations under CIP. It is our hypothesis that the modulations of the BBB under CIP, are mediated via a central signaling pathway. First, to investigate the involvement of neuronal input from pain activity on alterations in BBB, we developed a method for inhibiting the nociceptive input from the paw. Using a perineural injection of 0.75% bupivacaine into the right hind leg prior to CIP, we were able inhibit development thermal hyperalgesia induced by CIP, as tested by infrared heat stimulus, without effecting edema formation 1 h post CIP. Upon inhibition of nociception under CIP, there was an attenuation of both the changes in permeability and the changes in tight junction protein expression, with both returning to control levels. Next, we investigated intercellular adhesion molecule-1 (ICAM-1), a key signaling protein at the BBB, which in the presence of proinflammatory mediators, increases in expression leading to the activation of signaling pathways as well as morphological changes. We found a region specific increase in ICAM-1 mRNA and protein expression following CIP which directly correlated with increased expression of activated microglia. Finally, we investigated the influence activated microglia had on BBB permeability. Using an 0.150 mg intrathecal bolus injection of minocycline, a potent inhibitor of microglia activation (Klein and Cunha, 1995), we were able to inhibit the increased expression of activated microglia, and saw an attenuation of permeability to control levels. These findings suggest CIP induced BBB disruption is localized and has a central-mediated component independent of peripheral influence.