Tight Junction Regulation by Morphine and HIV-1 Tat Modulates Blood–Brain Barrier Permeability

Abstract

Human immunodeficiency virus (HIV)-1 patients who abuse opiates are at a greater risk of developing neurological complications of AIDS. Alterations in blood-brain barrier (BBB) integrity are associated with cytoskeletal disorganization and disruption of tight junction (TJ) integrity. We hypothesize that opiates in combination with HIV-1 viral proteins can modulate TJ expression in primary brain microvascular endothelial cells (BMVEC), thereby compromising BBB integrity and exacerbating HIV-1 neuropathogenesis. We investigated the effect of morphine and/or tat on the expression of TJ proteins ZO-1, JAM-2, Occludin and P-glycoprotein and the functional effects of TJ modulation in BMVEC. Morphine and/or tat, via the activation of pro-inflammatory cytokines, intracellular Ca(2+) release, and activation of myosin light chain kinase, modulated TJ expression resulting in decreased transendothelial electric resistance and enhanced transendothelial migration across the BBB. These studies may lead to the development of novel anti-HIV-1 therapeutics that target specific TJ proteins, thus preventing TJ disruption in opiate using HIV-1 patients.

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…These macrostructural changes have clear implications for drug and metabolite access into the CNS, as well as peripheral cell migration. Morphine alone (Mahajan et al, 2008) or morphine withdrawal (Sharma and Ali, 2006;Sharma et al, 2010) has been found to increase the leakiness of the blood-brain barrier, but this finding is not consistent in the literature (Mantz et al, 1993).…”

Recombinant Osteopontin Attenuates Brain Injury after Intracerebral Hemorrhage in Mice

“…ZO-1 is a peripheral tight junction protein that is found on the epithelial and endothelial cells membrane. Loss of ZO-1 from endothelial tight junction increases BBB permeability [27] and allows greater influx of blood-borne cells and substances into brain parenchyma, thus amplifying inflammation, leading to further parenchymal damage and edema formation [27].…”

Enhanced Pulmonary Arteriopathy in Simian Immunodeficiency Virus–infected Macaques Exposed to Morphine

“…Morphine, apart from exacerbating endothelial dysfunction in the presence of the HIV protein Tat (13), has been shown to stimulate both apoptosis and proliferation of vascular endothelial cells (14)(15)(16)(17). Based on these findings, we hypothesized that simian immunodeficiency virus (SIV)-infected rhesus macaques exposed chronically to morphine would demonstrate an accentuated pulmonary vascular arteriopathy.…”