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.

HIV-1 affects microglia and astroglia, which subsequently contributes to the neurodegenerative changes. Viral proteins cause neurotoxicity by direct action on the CNS cells or by activating glial cells to cause the release of cytokines, chemokines or neurotoxic substances. Opioid abuse has been postulated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) infection and AIDS. HIV-induced pathogenesis is exacerbated by opiate abuse and that the synergistic neurotoxicity is a direct effect of opiates on the CNS. Chemokines and their receptors have been implicated in the pathogenesis of neuroAIDS. Herein we describe the effects of morphine and/or gp120 on the expression of the genes for the beta-chemokine MIP-1beta and its receptors CCR3 and CCR5 by the U373 cells which are a human brain-derived astrocytoma/glioblastoma cell line. Our results indicate that treatment of U373 cells with morphine significantly downregulated the gene expression of the beta chemokine, MIP-1 beta, while reciprocally upregulating the expression of its specific receptors, CCR3 and CCR5 suggesting that the capacity of mu-opioids to increase HIV-1 co-receptor expression may promote viral binding, trafficking of HIV-1-infected cells, and enhanced disease progression. Additionally, opiates can enhance the cytotoxicity of HIV-1 viral protein gp120 via mechanisms that involve intracellular calcium modulation resulting in direct actions on astroglia, making them an important cellular target for HIV-opiate interactions.

Abstract-Both stimulatory and suppressive responses of the sympathetic nervous system to angiotensin II (AII) Key Words: sympathetic nervous system Ⅲ angiotensin II Ⅲ calcium Ⅲ calcium channel blockers Ⅲ norepinephrine Ⅲ inositol T he renin-angiotensin and sympathetic nervous systems are homeostatically interconnected by a complex series of mutually reinforcing and mutually inhibiting interactions. In general, each of these systems tends to reinforce the pressor effects of the other as the two systems act to defend arterial pressure. Sympathetic stimulation is a major controller of juxtaglomerular cell renin release through the actions of catecholamines on juxtaglomerular cell ␤ 1 receptors. 1 The angiotensin II (AII) subsequently generated in the bloodstream can exert positive feedback on sympathetic nervous activity by several complex mechanisms, including direct stimulatory actions of AII on central and peripheral sympathetic neuronal activity and catecholamine release. [1][2][3] In addition to its stimulatory effects, AII can also suppress sympathetic neuronal activity in vivo. In animals and humans, complex reflex inhibition occurs when increases in arterial pressure stimulate arterial baroreflexes to cause reflex suppression of sympathetic nervous outflow. A more confusing picture emerges in whole-animal experiments designed to isolate the contributions of the peripheral sympathetic nervous system: AII infusion can facilitate, 4 suppress, 5 or have no effect 6 on norepinephrine release from postganglionic sympathetic neurons. In humans, a similar pattern of sympathetic neural responses has been reported, with some studies showing increased norepinephrine spillover 3 and others showing no response 7 or decreased norepinephrine release 3,7,8 in response to AII. In other excitable cell types such as cardiomyocytes or vascular smooth muscle cells, a paradoxical response has also been reported. AII treatment was shown to increase cytosolic calcium ([Ca 2ϩ ]i) by stimulation of IP 3 -dependent pathways 9,10 and was also reported to decrease [Ca 2ϩ ]i through enhanced calcium efflux. 11,12 The current studies were undertaken to examine the effects of AII on neuronal [Ca 2ϩ ]i and to investigate whether alterations in [Ca 2ϩ ]i play a role in the apparent "bidirectional" excitatory and suppressive responses to AII seen in sympathetic neurons studied in vivo. Using isolated primary sympathetic neurons from rats, we first related neuronal responses to the dose of AII and to the baseline [Ca 2ϩ ]i. To confirm that the same neuron is capable of both stimulatory and suppressive responses to AII, cells with spontaneously low [Ca 2ϩ ]i were exposed to a Ca 2ϩ ionophore and cells with spontaneously high [Ca 2ϩ ]i were exposed to nifedipine. We used losartan to investigate the role of the AT 1 receptors and confirmed IP 3 pathway dependency with an IP 3 receptor blocker and by prior

Aspirin-induced platelet inhibition may be more potent following bariatric surgery. The mechanisms behind this improvement require further investigation.