The nociceptin?orphanin FQ receptor antagonist UFP-101 reduces microvascular inflammation to lipopolysaccharide in vivo..pdf (656.75 kB)
The Nociceptin/Orphanin FQ Receptor Antagonist UFP-101 Reduces Microvascular Inflammation to Lipopolysaccharide In Vivo
journal contribution
posted on 2015-07-20, 08:33 authored by Z. L. Brookes, E. N. Stedman, N. J. Brown, Christopher P. Hebbes, R. Guerrini, G. Calo, C. S. Reilly, David G. LambertMicrovascular inflammation occurs during sepsis and the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) is known to regulate inflammation. This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory effects of the NOP antagonist UFP-101 (University of Ferrara Peptide-101) in an animal model of sepsis (endotoxemia). Male Wistar rats (220 to 300 g) were administered lipopolysaccharide (LPS) for 24 h (-24 h, 1 mg kg(-1); -2 h, 1 mg kg(-1) i.v., tail vein). They were then either anesthetised for observation of the mesenteric microcirculation using fluorescent in vivo microscopy, or isolated arterioles (~200 µm) were studied in vitro with pressure myography. 200 nM kg(-1) fluorescently labelled N/OFQ (FITC-N/OFQ, i.a., mesenteric artery) bound to specific sites on the microvascular endothelium in vivo, indicating sparse distribution of NOP receptors. In vitro, arterioles (~200 µm) dilated to intraluminal N/OFQ (10(-5)M) (32.6 + 8.4%) and this response was exaggerated with LPS (62.0 +7.9%, p=0.031). In vivo, LPS induced macromolecular leak of FITC-BSA (0.02 g kg(-1) i.v.) (LPS: 95.3 (86.7 to 97.9)%, p=0.043) from post-capillary venules (<40 µm) and increased leukocyte rolling as endotoxemia progressed (p=0.027), both being reduced by 150 nmol kg(-1) UFP-101 (i.v., jugular vein). Firstly, the rat mesenteric microcirculation expresses NOP receptors and secondly, NOP function (ability to induce dilation) is enhanced with LPS. UFP-101 also reduced microvascular inflammation to endotoxemia in vivo. Hence inhibition of the microvascular N/OFQ-NOP pathway may have therapeutic potential during sepsis and warrants further investigation.
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Citation
PLoS One, 2013, 8 (9), e74943Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular SciencesVersion
- VoR (Version of Record)
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PLoS OnePublisher
Public Library of Scienceeissn
1932-6203Acceptance date
2013-08-07Copyright date
2013Available date
2015-07-20Publisher DOI
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074943Language
enAdministrator link
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