The nociceptin/orphanin FQ receptor antagonist UFP-101 reduces microvascular inflammation to lipopolysaccharide in vivo.

Abstract

Microvascular 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.

• Authors: Zoë L S Brookes, Emily N Stedman, Nicola J Brown, Christopher P Hebbes, Remo Guerrini, Girolamo Calo, Charles S Reilly, David G Lambert
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e74943 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24086402 (Publication Type: Journal Article)

Chemical References

• (Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)
• Narcotic Antagonists
• Opioid Peptides
• Receptors, Opioid
• Recombinant Proteins
• nociceptin
• Fluorescein-5-isothiocyanate
• Nociceptin Receptor

Topics

• Animals
• CHO Cells
• Cardiovascular System (drug effects, pathology, physiopathology)
• Cricetinae
• Cricetulus
• Fluorescein-5-isothiocyanate (metabolism)
• Inflammation (metabolism, pathology)
• Leukocyte Rolling (drug effects)
• Male
• Microcirculation (drug effects)
• Microvessels (drug effects, pathology)
• Narcotic Antagonists
• Opioid Peptides (metabolism, pharmacology)
• Rats
• Rats, Wistar
• Receptors, Opioid (metabolism)
• Recombinant Proteins (metabolism)
• Nociceptin Receptor