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

Abstract

The blood-brain barrier (BBB) is a dynamic system which maintains brain homeostasis and limits CNS penetration via interactions of transmembrane and intracellular proteins. Inflammatory pain (IP) is a condition underlying several diseases with known BBB perturbations, including stroke, Parkinson's, multiple sclerosis and Alzheimer's. Exploring the underlying pathology of chronic IP, we demonstrated alterations in BBB paracellular permeability with correlating changes in tight junction (TJ) proteins: occludin and claudin-5. The present study examines the IP-induced molecular changes leading to a loss in functional BBB integrity. IP was induced by injection of Complete Freund's Adjuvant (CFA) into the plantar surface of the right hindpaw of female Sprague-Dawley rats. Inflammation and hyperalgesia were confirmed, and BBB paracellular permeability was assessed by in situ brain perfusion of [ 14 C]sucrose (paracellular diffusion marker). The permeability of the BBB was significantly increased at 24 and 72 h post-CFA. Analysis of the TJ proteins, which control the paracellular pathway, demonstrated decreased claudin-5 expression at 24 h, and an increase at 48 and 72 h post-injection. Occludin expression was significantly decreased 72 h post-CFA. Expression of junction adhesion molecule-1 (JAM-1) increased 48 h and decreased by 72 h post-CFA. Confocal microscopy demonstrated continuous expression of both occludin and JAM-1, each co-localizing with ZO-1. The increased claudin-5 expression was not limited to the junction. These results provide evidence that chronic IP causes dramatic alterations in specific cytoarchitectural proteins and demonstrate alterations in molecular properties during CFA, resulting in significant changes in BBB paracellular permeability.

Nociceptive inhibition prevents inflammatory pain induced changes in the blood–brain barrier

“…The TJ consists of transmembrane proteins (occludin and claudins) that interact on adjacent endothelial cells to form a physical barrier to paracellular diffusion (Fanning et al, 1999) with accessory proteins such as ZO-1 and ZO-2 also playing an integral role (Anderson et al, 1995). Permeability changes have been correlated with alterations in expression and localization of ZO-1, claudin-5 and occludin ( (Brooks et al, 2006); (Huber et al, 2001a); (Lee et al, 2004)). In this study we examined the expression of ZO-1, occludin and claudin-5 under conditions of peripheral nerve block of CIP to help clarify the association between nociceptive input and changes in BBB integrity.…”

Central histamine H3receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

“…Induction of EAE by active immunization with MOG and adjuvants obviously involves a peripheral initiation phase. Two components of this immunization are CFA and PTX, both of which are known to increase BBB permeability (33)(34)(35)(36) and cytokine and inflammatory mediator levels within the CNS rapidly after injection. Specifically, either CFA or PTX can elicit IL-1␤, TNF-␣, and/or IL-6 production in the CNS within 2 h after their injection (37)(38)(39)(40)(41)(42).…”

Inflammatory Pain Signals an Increase in Functional Expression of Organic Anion Transporting Polypeptide 1a4 at the Blood-Brain Barrier

“…Our laboratory has shown, in vivo, modifications in functional BBB integrity and changes in CNS drug delivery induced by peripheral inflammatory pain (Huber et al, 2001;Hau et al, 2004;Brooks et al, 2006Brooks et al, , 2008Seelbach et al, 2007;Campos et al, 2008;Ronaldson et al, 2009). The critical link between inflammation in peripheral tissues and altered BBB permeability and/or transport may involve changes in serum cytokines such as transforming growth factor-␤ (TGF-␤).…”