Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) were identified in the mid 90s as a novel peptidergic system structurally related to opioids. A growing body of preclinical evidence suggests that blockade of NOP receptors evokes antidepressant-like actions. These have been explored using a range of compounds (peptide and non peptide antagonists), across different species (rat and mouse) and assays (behavioral despair and chronic mild stress) suggesting a robust and consistent antidepressant-like effect. Moreover, rats and mice knockout for the NOP receptor gene display an antidepressant-like phenotype in behavioral despair assays. Electrophysiological, immunohistochemical and neurochemical studies point to an important role played by monoaminergic systems, particularly 5-HTergic, in mediating the antidepressant-like properties of NOP antagonists. However other putative mechanisms of action, including modulation of the CRF system, circadian rhythm and a possible neuroendocrine-immune control might be involved. A close relationship between the N/OFQ-NOP receptor system and stress responses is well described in the literature. Stressful situations also alter endocrine, behavioral and neurochemical parameters in rats and chronic administration of a NOP antagonist restored these alterations. Interestingly, clinical findings showed that plasma N/OFQ levels were significantly altered in major and post-partum depression, and bipolar disease patients. Collectively, data in the literature support the notion that blockade of NOP receptor signaling could be a novel and interesting strategy for the development of innovative antidepressants.
Keywords: 5-HT; 5-HT neurotransmission; ACTH; Accumbens nucleus; Amy; BDNF; CRF; DRN; HPA; Hipp; LC; MAPK; Mood disorders; N/OFQ; NAc; NOP antagonists; NOP receptor; NTS; Nociceptin/orphanin FQ; PFC; POMC; Stress; VTA; adrenocorticotropic hormone; amygdala; brain derived neurotrophic factor; corticotropin release factor; dorsal raphe nucleus; hippocampus; hypothalamus–pituitary–adrenal axis; locus ceruleus; mitogen-activated protein kinase; nociceptin/orphanin FQ; nociceptin/orphanin FQ peptide receptor; nucleus of the solitary tract; ppN/OFQ; prefrontal cortex; prepronociceptin/orphanin FQ; proopiomelanocortin; serotonin; ventral tegmental area.
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