NociceptinOrphanin

Nociceptin/orphanin FQ, often abbreviated as N/OFQ, is a neuropeptide that serves as the endogenous ligand for the nociceptin receptor (NOP, also known as ORL1). It is produced from the PNOC gene, which encodes a larger prepronociceptin precursor that is processed to yield the mature nociceptin/orphanin FQ, a 17-amino-acid peptide.

The nociceptin receptor is a G protein-coupled receptor that is pharmacologically distinct from the classical opioid receptors (mu, delta, and kappa). It primarily couples to Gi/o proteins, leading to inhibition of adenylyl cyclase and reduced cyclic AMP, activation of GIRK channels, and diminished calcium influx. This signaling modulates neurotransmitter release and various neuronal circuits.

NOC/NOP signaling is widely distributed in the central nervous system, with notable expression in the cortex, hippocampus, amygdala, periaqueductal gray, and hypothalamus, as well as in the spinal cord and peripheral tissues such as immune cells and the gut. The N/OFQ system influences nociception, stress and anxiety responses, learning and memory, appetite and energy balance, reward pathways, and respiratory control.

Physiological and clinical relevance is centered on the system’s complex effects on pain, mood, and behavior. NOP agonists can produce analgesia in certain contexts but may yield anxiogenic or sedative effects in others; antagonists and biased ligands are also studied for potential therapeutic benefits. Research continues to explore NOP-targeted strategies for pain management, anxiety, depression, and substance use disorders.

Discovery and terminology: Orphanin FQ was identified in the 1990s as the endogenous ligand for the then-orphan nociceptin receptor; the ligand is also called nociceptin, and the receptor is referred to as NOP or ORL1.