Journal of Amino Acids

Review Article

NOP Receptor Ligands as Potential Agents for Inflammatory and Autoimmune Diseases

Table 1

Mechanisms underlying some immunoregulatory activities triggered by NOP receptor activation.


Biological effects related to N/OFQ or its interaction in the neuroimmune axis	Mechanisms	Animal conditions or cell type	Ref

Bacterial products (LPS) and inflammatory cytokines (IL-1β and TNF-α) increase the expression of N/OFQ in astrocytes	Dependent on ERK, p38 MAPK, and NF-κB activation	Primary rat astrocytes culture	[33]

LPS induce N/OFQ expression in dorsal root ganglion (DRG) neurons	The complex TLR-4-MD-1 seems to be a functional receptor of neurons for LPS	DRG neurons obtained from mice	[77]

N/OFQ induces vasodilatation and hyperemia in acutely inflamed rat knees	Dependent of mast cells, and circulating leukocytes, which produces proinflammatory factors that stimulate capsaicin-sensitive nerves leading to release of SP, CGRP and VIP	Anesthetized rats (kaolin/carragee an arthritis model)	[78]

Increased vascular permeability in rat skin by local application of nociceptin	Histamine released from mast cells	Wistar rats, peritoneal mast cells isolated	[79]

N/OFQ i.v. injection induces hypotension, vasodilatation, vascular permeability, leukocytes rolling, and adhesion	Vasodilation and inflammation dependent, of histamine released by mast cells	Wistar rats	[80]

N/OFQ elicits in mice itch and leukotriene B₄ production	Not clear	ICR mice, keratinocytes from mice	[81]

N/OFQ induces chemotaxis of neutrophils in vitro and leukocytes recruitment in vivo	The chemotaxis were Ca²⁺ independent, and leukocytes infiltration into air pouches cavities were inhibited by 15-Epi-Lipoxin A₄ treatment	Human PMN-isolated and murine air pouches model	[31]

Human neutrophils secrete preformed N/OFQ upon degranulation induced by microbial-derived N-formylated protein	N/OFQ prevents cAMP elevation in fMLP-stimulated PMNs acting as an activating signal	Human neutrophils	[32]

NOP-deficient mice developed attenuated colitis when orally treated with dextran sulfate sodium	Decreased expression of MadCAM-1 and significant reduction in the number of lymphocytes, macrophages and neutrophils in colonic mucosa	NOP deficient and wild-type C57BL6 mice	[59]

Pharmacological blockade of NOP receptor decreases rate mortality and systemic inflammation in septic rats	Control of bacteria spread (peritoneal cavity and blood) and decreased lung infiltration and serum levels of TNF-α, IL-1β, and CCL2	Rats subjected to CLP	[55]

N/OFQ decreases SEB-activated T-cell proliferation	Induction of active IDO expression in T cells by a mechanism involving IFN-γ, TGF-β, prostaglandin, and nitric oxide	SEB-activated CD4⁺ T cells	[42]

Modulation of genes transcription involved in the neuroimmune axis functions	N/OFQ induces cell signaling via several intracellular pathways leading to MAP kinase activation, PKC activation, NFκB nuclear translocation, and hence gene transcriptions	Human neuroblastoma SH-SY5Y cells, CHO transfected cells	[82–85]

CCL2: chemokine (C-C motif) ligand 2; CGRP: calcitonin gene-related peptide; CLP: cecal ligation and puncture; ERK: extracellular signal-regulated kinase; fMLP: formyl-methionyl-leucyl-phenylalanin; IDO: indoleamine 2,3-dioxygenase; MAdCAM-1: mucosal addresin cell adhesion molecule-1; MAPK: mitogen-activated protein kinase; MD-1: myeloid differentiation protein-1; NFκB: nuclear factor Kappa B; PMN: polymorphonuclear neutrophil; SP: substance P; TLR4: toll-like receptor 4; VIP: vasoactive intestinal peptide.