|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
|(what is: / ?)|
|Locus||Chr. 8 p21|
Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor (NOP, ORL-1). It is derived from the prepronociceptin protein, as are a further 2 peptides, nocistatin & NocII. The gene coding for prepronociceptin is located on Ch8p21 in humans.
Nociceptin acts at the Nociceptin receptor (NOP receptor) formerly known as ORL1. Nociceptin is the first example of reverse pharmacology; the NOP receptor was discovered before the endogenous ligand which was discovered by two separate groups in 1995. Nociceptin is an opioid-related peptide, but it does not act at the classic opioid receptors (namely, mu, kappa, and delta opioid receptors), and its actions are not antagonized by the opioid antagonist naloxone. Nociceptin is a potent anti-analgesic. Nociceptin is widely distributed in the CNS; it is found in many regions of the hypothalamus, brainstem, and forebrain, as well as in the ventral horn and dorsal horn of the spinal cord. The NOP receptor is also widely distributed in the brain, including in the cortex, anterior olfactory nucleus, lateral septum, hypothalamus, hippocampus, amygdala, central gray, pontine nuclei, interpeduncular nucleus, substantia nigra, raphe complex, locus coeruleus, and spinal cord.
Roles of Nociceptin
Since its discovery, nociceptin has enjoyed great interest. It is found extensively across the body and there is potential for future medicines to target the system.
The effects of nociceptin on pain have been widely described and the N/OFQ-NOP system is found in central and peripheral nervous tissue, where it is well placed to modulate nociception. Unlike morphine and other opioids that are used to alleviate pain, nociceptin's role in nociception are not straight forward. Administeration of N/OFQ in the brain causes increased sensations of pain (hyperalgesia). There is substantial evidence to suggest that nociceptin is involved in opioid-induced hyperalgesia When administered to the spinal cord, nociceptin produces similar effects to classical opioids.
There are various studies on animals that suggest that the N/OFQ-NOP system has a part to play in both anxiety and depression. It appears that nociceptin is an anxiolytic but also seems to perpetuate depression as preventing N/OFQ from binding to NOP seems to improve depression.
The N/OFQ-NOP system has also been implicated in control of the cardiovascular and renal systems and there is evidence to suggest nociceptin may be involved in the immune system and sepsis. A study at the University of Leicester looked at patients critically ill with sepsis and found that blood N/OFQ levels were significantly higher in patients who died within thirty days than survivors.
- Okuda-Ashitaka, E; Minami, T; Tachibana, S; Yoshihara, Y; Nishiuchi, Y; Kimura, T; Ito, S. (Mar 1998). "Nocistatin, a peptide that blocks nociceptin action in pain transmission". Nature 392 (6673): 286–9. doi:10.1038/32660. PMID 9521323.
- Mollereau, C; Simons, MJ; Soularue, P; Liners, F; Vassart, G; Meunier, JC; Parmentier, M. (Aug 1996). "Structure, tissue distribution, and chromosomal localization of the prepronociceptin gene". Proceedings of the National Academy of Sciences USA 93 (16): 8666–70. doi:10.1073/pnas.93.16.8666. PMC 38730. PMID 8710928.
- Meunier, JC; Mollereau, C (1995). "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor". Nature 377 (6549): 532–535. doi:10.1038/377532a0. PMID 7566152.
- Lambert, DG (Aug 2008). "The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential.". Nature reviews. Drug discovery 7 (8): 694–710. doi:10.1038/nrd2572. PMID 18670432.
- Meunier, JC; Mollereau, C; Toll, L; Suaudeau, C; Moisand, C; Alvinerie, P; Butour, JL; Guillemot, JC; Ferrara, P; Monsarrat, B (Oct 12, 1995). "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor.". Nature 377 (6549): 532–5. doi:10.1038/377532a0. PMID 7566152.
- Pan, Z; Hirakawa, N; Fields, HL (May 2000). "A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin.". Neuron 26 (2): 515–22. doi:10.1016/s0896-6273(00)81183-6. PMID 10839369.
- Katsuyama, S; Mizoguchi, H; Komatsu, T; Sakurada, C; Tsuzuki, M; Sakurada, S; Sakurada, T (Jul 2011). "Antinociceptive effects of spinally administered nociceptin/orphanin FQ and its N-terminal fragments on capsaicin-induced nociception.". Peptides 32 (7): 1530–5. doi:10.1016/j.peptides.2011.05.028. PMID 21672568.
- Jenck, F; Moreau, JL; Martin, JR; Kilpatrick, GJ; Reinscheid, RK; Monsma FJ, Jr; Nothacker, HP; Civelli, O (Dec 23, 1997). "Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress.". Proceedings of the National Academy of Sciences of the United States of America 94 (26): 14854–8. doi:10.1073/pnas.94.26.14854. PMID 9405703.
- Gavioli, EC; Vaughan, CW; Marzola, G; Guerrini, R; Mitchell, VA; Zucchini, S; De Lima, TC; Rae, GA; Salvadori, S; Regoli, D; Calo', G (Jun 2004). "Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice.". Naunyn-Schmiedeberg's archives of pharmacology 369 (6): 547–53. doi:10.1007/s00210-004-0939-0. PMID 15197534.
- Thomas, R; Stover, C; Lambert, DG; Thompson, JP (Apr 12, 2014). "Nociceptin system as a target in sepsis?". Journal of anesthesia 28 (5): 759–67. doi:10.1007/s00540-014-1818-6. PMID 24728719.
- Williams, J. P.; Thompson, J. P.; Young, S. P.; Gold, S. J.; McDonald, J.; Rowbotham, D. J.; Lambert, D. G. (1 May 2008). "Nociceptin and urotensin-II concentrations in critically ill patients with sepsis". British Journal of Anaesthesia 100 (6): 810–814. doi:10.1093/bja/aen093.
- nociceptin at the US National Library of Medicine Medical Subject Headings (MeSH)
- prepronociceptin at the US National Library of Medicine Medical Subject Headings (MeSH)