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 (10-5M) (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.

Endogenous Nociceptin System Involvement in Stress Responses and Anxiety Behavior

“…Endogenous N/OFQ function is also implicated in the response to systemic inflammation following lipopolysaccharide administration. Peptidic NOP receptor antagonist, UFP-101, has been shown to inhibit microvascular inflammation in vivo (Brookes et al, 2013), and we have shown that UFP-101 suppresses the hypothalamo-pituitary-adrenal (HPA) axis response to peripheral LPS challenge (Leggett, Dawe, Jessop, & Fulford, 2009). These findings are potentially of significant clinical relevance in the context that patients with more severe cases of sepsis have significantly higher concentrations of plasma N/OFQ and worse outcomes .…”

State of the art papers HLA-DR expression, cytokines and bioactive lipids in sepsis

“…This indicates that enhanced plasma levels of nociceptin indicate continuation of the sepsis process [58] whereas a decrease in their levels may indicate recovery.…”

Nociceptin system as a target in sepsis?

“…20 Furthermore, we showed that antagonising NOP with UFP-101 during LPS-induced sepsis produced anti-inflammatory effects (such as decreased macromolecular leak and reduced leucocyte rolling) in post-capillary venules.…”

“…20 There is also evidence to suggest that N/OFQ may have the ability to recruit neutrophils directly.…”