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Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells:
Hongxiu Wen1, Yaman Lu, Honghong Yao
1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Abstract:
Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Morphine, often abused by HIV-infected patients, is known to accelerate neuroinflammation associated with HIV-1 infection. Detailed molecular mechanisms of morphine action however, remain poorly understood. Platelet-derived growth factor (PDGF) has been implicated in a number of pathological conditions, primarily due to its potent mitogenic and permeability effects. Whether morphine exposure results in enhanced vascular permeability in brain endothelial cells, likely via induction of PDGF, remains to be established. In the present study, we demonstrated morphine-mediated induction of PDGF-BB in human brain microvascular endothelial cells, an effect that was abrogated by the opioid receptor antagonist-naltrexone. Pharmacological blockade (cell signaling) and loss-of-function (Egr-1) approaches demonstrated the role of mitogen-activated protein kinases (MAPKs), PI3K/Akt and the downstream transcription factor Egr-1 respectively, in morphine-mediated induction of PDGF-BB. Functional significance of increased PDGF-BB manifested as increased breach of the endothelial barrier as evidenced by decreased expression of the tight junction protein ZO-1 in an in vitro model system. Understanding the regulation of PDGF expression may provide insights into the development of potential therapeutic targets for intervention of morphine-mediated neuroinflammation.
Insights
Morphine abuse in HIV-1 patients accelerates neuroinflammation by increasing PDGF-BB in brain endothelial cells, compromising the blood-brain barrier. This effect is mediated by MAPK and PI3K/Akt signaling pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- HIV-1 infection and drug abuse present complex health challenges, with morphine abuse exacerbating neuroinflammation.
- The precise molecular mechanisms underlying morphine's neuroinflammatory effects, particularly concerning the blood-brain barrier, are not fully understood.
Purpose of the Study:
- To investigate whether morphine exposure enhances vascular permeability in brain endothelial cells.
- To determine if Platelet-Derived Growth Factor (PDGF) mediates morphine-induced vascular permeability.
- To elucidate the molecular signaling pathways involved in morphine-mediated PDGF induction.
Main Methods:
- Utilized human brain microvascular endothelial cells to study morphine's effects.
- Assessed PDGF-BB induction and its dependence on opioid receptors using naltrexone.
- Employed pharmacological inhibitors and loss-of-function approaches to identify key signaling molecules like MAPKs, PI3K/Akt, and Egr-1.
- Evaluated endothelial barrier integrity by measuring the expression of tight junction protein ZO-1.
Main Results:
- Morphine significantly induced PDGF-BB expression in brain endothelial cells.
- The morphine-induced PDGF-BB production was blocked by the opioid receptor antagonist naltrexone.
- Mitogen-activated protein kinases (MAPKs), PI3K/Akt signaling, and the transcription factor Egr-1 were identified as crucial mediators of morphine-induced PDGF-BB.
- Increased PDGF-BB levels correlated with a compromised endothelial barrier, indicated by reduced ZO-1 expression.
Conclusions:
- Morphine exposure induces PDGF-BB production in brain endothelial cells via MAPK and PI3K/Akt/Egr-1 signaling pathways.
- This induction leads to increased vascular permeability and compromised blood-brain barrier integrity.
- Understanding these mechanisms offers potential therapeutic targets for mitigating morphine-induced neuroinflammation in HIV-1 patients.
