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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.

The Nociceptin/Orphanin FQ Receptor Antagonist UFP-101 Reduces Microvascular Inflammation to Lipopolysaccharide In Vivo