Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs

Pharmacol Ther. 2013 Oct;140(1):10-25. doi: 10.1016/j.pharmthera.2013.05.008. Epub 2013 May 24.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Anxiety / metabolism
  • Humans
  • Mood Disorders / metabolism
  • Narcotic Antagonists*
  • Opioid Peptides / physiology*
  • Receptors, Opioid / physiology
  • Stress, Psychological / metabolism

Substances

  • Antidepressive Agents
  • Narcotic Antagonists
  • Opioid Peptides
  • Receptors, Opioid
  • nociceptin
  • nociceptin receptor