Chemistry:Nociceptin

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Nociceptin
Nociceptin.png
Names
Other names
Orphanin FQ
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
MeSH nociceptin
UNII
Properties
C79H129N27O22
Molar mass 1809.04
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):
prepronociceptin
Identifiers
SymbolPNOC
NCBI gene5368
HGNC9163
OMIM601459
RefSeqNM_006228
UniProtQ13519
Other data
LocusChr. 8 p21

Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor (NOP, ORL-1). Nociceptin acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers; its activation is associated with brain functions such as pain sensation and fear learning.

The gene coding for prepronociceptin is located on Ch8p21 in humans.[1] Nociceptin is derived from the prepronociceptin protein, as are a further two peptides, nocistatin and NocII, both of which inhibit N/OFQ receptor function.[2] 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.[3][4]

Roles of nociceptin

Since its discovery, nociceptin has been of great interest to researchers. Nociceptin is a peptide related to the opioid class of compounds (ex. morphine and codeine), but it does not act at the classic opioid receptors (namely, mu, kappa, and delta opioid receptors) which typically act as pain relievers. Nociceptin is widely distributed in the CNS; it is found in the hypothalamus, brainstem, and forebrain, as well as in the ventral and dorsal horns of the spinal cord. The NOP receptor is also widely distributed throughout areas of the brain, including 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.[5]

Pain

The N/OFQ-NOP system is found in central and peripheral nervous tissue, where it is well placed to modulate nociception, or the body's sensation of pain.[1] Unlike morphine and other opioids that are used to alleviate pain, nociceptin's role in nociception is not straightforward. Administration of N/OFQ in the brain causes increased sensations of pain (hyperalgesia).[3] This makes it unique from classic opioid peptides, which typically act as analgesics (pain relievers), as it means that nociceptin can even counteract analgesia, thus acting as an antiopioid. Additionally, blocking the nociceptin receptor can lead to an increased pain threshold and a decreased tolerance development to analgesic opioids. As such, nociceptin has a lower risk of addiction than many pain relievers that are currently used.[6] Recent studies have proposed that this anti-analgesic function of nociceptin stems from the inhibition of the periaqueductal grey, which controls pain modulation from the central nervous system. This effect of nociceptin may lead to its future use as a method to reduce morphine dosage and decrease the development of tolerance and dependence.[5] When administered to the spinal cord, nociceptin produces similar analgesic effects to classical opioids.[7]

Mood disorders

There are various studies on animals that suggest that the N/OFQ-NOP system has a part to play in both anxiety and depression.[8] It appears that nociceptin is an anxiolytic (anxiety inhibitor) but also seems to perpetuate depression, since preventing N/OFQ from binding to NOP seems to improve depression.[9][10]

Drug abuse medications

The NOP receptor has shown potential as a target for medications designed to alleviate the effects of substance abuse disorders. Areas in the hypothalamus and amygdala that correlate to the reward process of drug abuse have been found to contain NOP receptors. Nociceptin has also been found to inhibit dopamine production related to the reward process. Specifically, nociceptin acts to inhibit neural rewards induced by drugs such as amphetamines, morphine, cocaine, and especially alcohol in animal models, though the exact mechanism of this has not yet been proven. Additionally, nociceptin may have lower tolerance development than drugs such as morphine. This was shown when nociceptin compounds were used as a pain medication substitution for morphine. Nociceptin also has therapeutic capabilities for addictions to multiple drugs, potentially playing a role in compounds that have decreased withdrawal tendencies (such as muscle aches, anxiety, and restlessness).[6]

Learning and memory

In animal studies, the N/OFQ-NOP receptor pathway has also been found to play both positive and negative roles in both learning and memory. For example, malfunctions in this pathway are linked to altered fear learning in brain disorders such as post-traumatic stress disorder (PTSD). As such, the receptor pathway maintains homeostatic responses to fear and stressful situations.[11] Nociceptin could also play an inhibitory role in memory function, as some studies show that it impairs spatial learning in vivo, while inhibiting long term potentiation and synaptic transmission in vitro.[5]

Cardiovascular system

The N/OFQ-NOP system has also been implicated in control of the cardiovascular system, as nociceptin administration has led to high blood pressure and bradycardia. Nociceptin has significant effects on cardiovascular parameters such as blood pressure and heart rate that vary by species, as it is excitatory for rodents yet inhibitory for sheep.[5]

Renal system

In the renal system, nociceptin plays a role in water balance, electrolyte balance, and arterial blood pressure regulation. It has also shown potential as a diuretic treatment for alleviating water-retaining diseases.[5]

Immune system

Additional research suggests that nociceptin may be involved in the immune system and sepsis.[12] A study at the University of Leicester looked at patients who were critically ill with sepsis and found that blood N/OFQ levels were significantly higher in patients who died within thirty days in comparison to survivors.[13]

Digestive system

In the gut, nociceptin has been found to have varying effects on stomach and intestinal contractility while also stimulating the increased consumption of food. Additional studies have shown that nociceptin may have an effect as an anti-epileptic drug component.[5]

See also

References

  1. ↑ 1.0 1.1 "Structure, tissue distribution, and chromosomal localization of the prepronociceptin gene". Proceedings of the National Academy of Sciences of the United States of America 93 (16): 8666–70. August 1996. doi:10.1073/pnas.93.16.8666. PMID 8710928. Bibcode: 1996PNAS...93.8666M. 
  2. ↑ "Nocistatin, a peptide that blocks nociceptin action in pain transmission". Nature 392 (6673): 286–9. March 1998. doi:10.1038/32660. PMID 9521323. Bibcode: 1998Natur.392..286O. 
  3. ↑ 3.0 3.1 "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor". Nature 377 (6549): 532–5. October 1995. doi:10.1038/377532a0. PMID 7566152. Bibcode: 1995Natur.377..532M. 
  4. ↑ Reinscheid, R. K.; Nothacker, H.-P.; Bourson, A.; Ardati, A.; Henningsen, R. A.; Bunzow, J. R.; Grandy, D. K.; Langen, H. et al. (1995-11-03). "Orphanin FQ: A Neuropeptide That Activates an Opioidlike G Protein-Coupled Receptor" (in en). Science 270 (5237): 792–794. doi:10.1126/science.270.5237.792. ISSN 0036-8075. PMID 7481766. Bibcode: 1995Sci...270..792R. https://www.science.org/cgi/doi/10.1126/science.270.5237.792. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Pharmacology of nociceptin and its receptor: a novel therapeutic target". British Journal of Pharmacology 129 (7): 1261–83. April 2000. doi:10.1038/sj.bjp.0703219. PMID 10742280. 
  6. ↑ 6.0 6.1 "The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications". Current Topics in Medicinal Chemistry 11 (9): 1151–6. 2011-01-01. doi:10.2174/156802611795371341. PMID 21050175. 
  7. ↑ "Antinociceptive effects of spinally administered nociceptin/orphanin FQ and its N-terminal fragments on capsaicin-induced nociception". Peptides 32 (7): 1530–5. July 2011. doi:10.1016/j.peptides.2011.05.028. PMID 21672568. 
  8. ↑ "The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential". Nature Reviews. Drug Discovery 7 (8): 694–710. August 2008. doi:10.1038/nrd2572. PMID 18670432. 
  9. ↑ "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. December 1997. doi:10.1073/pnas.94.26.14854. PMID 9405703. Bibcode: 1997PNAS...9414854J. 
  10. ↑ "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. June 2004. doi:10.1007/s00210-004-0939-0. PMID 15197534. 
  11. ↑ "Nociceptin and the nociceptin receptor in learning and memory". Progress in Neuro-Psychopharmacology & Biological Psychiatry 62: 45–50. October 2015. doi:10.1016/j.pnpbp.2015.02.007. PMID 25724763. 
  12. ↑ "Nociceptin system as a target in sepsis?". Journal of Anesthesia 28 (5): 759–67. October 2014. doi:10.1007/s00540-014-1818-6. PMID 24728719. https://figshare.com/articles/journal_contribution/10139792. 
  13. ↑ "Nociceptin and urotensin-II concentrations in critically ill patients with sepsis". British Journal of Anaesthesia 100 (6): 810–4. June 2008. doi:10.1093/bja/aen093. PMID 18430746. 

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