Nociceptin: Difference between revisions

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{{infobox protein

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'''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.<ref name="Mollereau 1996">{{cite journal | vauthors = Mollereau C, Simons MJ, Soularue P, Liners F, Vassart G, Meunier JC, Parmentier M | title = Structure, tissue distribution, and chromosomal localization of the prepronociceptin gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 16 | pages = 8666–70 | date = August 1996 | pmid = 8710928 | pmc = 38730 | doi = 10.1073/pnas.93.16.8666 | bibcode = 1996PNAS...93.8666M | doi-access = free }}</ref> Nociceptin is derived from the prepronociceptin [[protein]], as are a further two peptides, [[nocistatin]] and [[NocII]], both of which inhibit N/OFQ receptor function.<ref name="Okuda-Ashitaka">{{cite journal | vauthors = Okuda-Ashitaka E, Minami T, Tachibana S, Yoshihara Y, Nishiuchi Y, Kimura T, Ito S | title = Nocistatin, a peptide that blocks nociceptin action in pain transmission | journal = Nature | volume = 392 | issue = 6673 | pages = 286–9 | date = March 1998 | pmid = 9521323 | doi = 10.1038/32660 | bibcode = 1998Natur.392..286O | s2cid = 4414426 }}</ref> 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.<ref name="Meunier et al. Isolation of N/OFQ"/><ref>{{Cite journal|last1=Reinscheid|first1=R. K.|last2=Nothacker|first2=H.-P.|last3=Bourson|first3=A.|last4=Ardati|first4=A.|last5=Henningsen|first5=R. A.|last6=Bunzow|first6=J. R.|last7=Grandy|first7=D. K.|last8=Langen|first8=H.|last9=Monsma|first9=F. J.|last10=Civelli|first10=O.|date=1995-11-03|title=Orphanin FQ: A Neuropeptide That Activates an Opioidlike G Protein-Coupled Receptor|url=https://www.science.org/cgi/doi/10.1126/science.270.5237.792|journal=Science|language=en|volume=270|issue=5237|pages=792–794|doi=10.1126/science.270.5237.792|pmid=7481766|bibcode=1995Sci...270..792R |s2cid=38117854|issn=0036-8075}}</ref>

== Roles of nociceptin ==

Since its discovery, nociceptin has been of great interest to researchers. Nociceptin is a [[peptide]] related to the [[Κ-opioid receptor|kappa opioid receptor]] ligand [[dynorphin A]],<ref>{{Citation |last=Koob |first=George F. |title=Chapter 2 - Introduction to the Neuropsychopharmacology of Drug Addiction |date=2014-01-01 |work=Drugs, Addiction, and the Brain |pages=29–63 |editor-last=Koob |editor-first=George F. |url=https://www.sciencedirect.com/science/article/pii/B9780123869371000027 |access-date=2024-04-23 |place=San Diego |publisher=Academic Press |doi=10.1016/b978-0-12-386937-1.00002-7 |isbn=978-0-12-386937-1 |last2=Arends |first2=Michael A. |last3=Le Moal |first3=Michel |editor2-last=Arends |editor2-first=Michael A. |editor3-last=Le Moal |editor3-first=Michel}}</ref> 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 [[Central nervous system|CNS]]; it is found in the [[hypothalamus]], [[brainstem]], and [[Prosencephalon|forebrain]], as well as in the [[Anterior horn (spinal cord)|ventral]] and [[posterior horn of spinal cord|dorsal horns]] of the [[spinal cord]]. The NOP receptor is also widely distributed throughout areas of the brain, including the [[Cerebral cortex|cortex]], [[anterior olfactory nucleus]], lateral [[Septal nuclei|septum]], [[hypothalamus]], [[hippocampus]], [[amygdala]], [[Periaqueductal gray|central gray]], [[Pons|pontine nuclei]], [[Interpeduncular fossa|interpeduncular nucleus]], [[substantia nigra]], [[Raphe nuclei|raphe complex]], [[locus coeruleus]], and [[spinal cord]].<ref name=":0" />

=== 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.<ref name="Mollereau 1996" /> 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]]).<ref name="Meunier et al. Isolation of N/OFQ">{{cite journal | vauthors = Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B | title = Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor | journal = Nature | volume = 377 | issue = 6549 | pages = 532–5 | date = October 1995 | pmid = 7566152 | doi = 10.1038/377532a0 | bibcode = 1995Natur.377..532M | s2cid = 4326860 | doi-access = free }}</ref> This makes it unique from classic opioid peptides, which typically act as [[analgesic]]s (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.<ref name=":1" /> Recent studies have proposed that this anti-analgesic function of nociceptin stems from the inhibition of the [[Periaqueductal gray|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.<ref name=":0">{{cite journal | vauthors = Calo' G, Guerrini R, Rizzi A, Salvadori S, Regoli D | title = Pharmacology of nociceptin and its receptor: a novel therapeutic target | journal = British Journal of Pharmacology | volume = 129 | issue = 7 | pages = 1261–83 | date = April 2000 | pmid = 10742280 | pmc = 1571975 | doi = 10.1038/sj.bjp.0703219 }}</ref> When administered to the spinal cord, nociceptin produces similar analgesic effects to classical opioids.<ref name="Katsuyama et al 2011">{{cite journal | vauthors = Katsuyama S, Mizoguchi H, Komatsu T, Sakurada C, Tsuzuki M, Sakurada S, Sakurada T | title = Antinociceptive effects of spinally administered nociceptin/orphanin FQ and its N-terminal fragments on capsaicin-induced nociception | journal = Peptides | volume = 32 | issue = 7 | pages = 1530–5 | date = July 2011 | pmid = 21672568 | doi = 10.1016/j.peptides.2011.05.028 | s2cid = 19982289 }}</ref>

===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.<ref name="Lambert 2008">{{cite journal|date=August 2008|title=The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential|journal=Nature Reviews. Drug Discovery|volume=7|issue=8|pages=694–710|doi=10.1038/nrd2572|pmid=18670432|vauthors=Lambert DG|s2cid=7466788}}</ref> 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.<ref>{{cite journal | vauthors = Jenck F, Moreau JL, Martin JR, Kilpatrick GJ, Reinscheid RK, Monsma FJ, Nothacker HP, Civelli O | title = Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 26 | pages = 14854–8 | date = December 1997 | pmid = 9405703 | doi = 10.1073/pnas.94.26.14854 | pmc=25127| bibcode = 1997PNAS...9414854J | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gavioli EC, Vaughan CW, Marzola G, Guerrini R, Mitchell VA, Zucchini S, De Lima TC, Rae GA, Salvadori S, Regoli D, Calo' G | title = Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 369 | issue = 6 | pages = 547–53 | date = June 2004 | pmid = 15197534 | doi = 10.1007/s00210-004-0939-0 | s2cid = 23140523 }}</ref>

=== 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).<ref name=":1">{{cite journal | vauthors = Zaveri NT | title = The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications | journal = Current Topics in Medicinal Chemistry | volume = 11 | issue = 9 | pages = 1151–6 | date = 2011-01-01 | pmid = 21050175 | pmc = 3899399 | doi=10.2174/156802611795371341}}</ref>

=== 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 [[Posttraumatic stress disorder|post-traumatic stress disorder]] (PTSD). As such, the receptor pathway maintains homeostatic responses to fear and stressful situations.<ref>{{cite journal | vauthors = Andero R | title = Nociceptin and the nociceptin receptor in learning and memory | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 62 | pages = 45–50 | date = October 2015 | pmid = 25724763 | pmc = 4458422 | doi = 10.1016/j.pnpbp.2015.02.007 }}</ref> 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|long term potentiation]] and synaptic transmission ''in vitro''.<ref name=":0" />

===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.<ref name=":0" />

=== 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.<ref name=":0" />

=== Immune system ===

Additional research suggests that nociceptin may be involved in the immune system and [[sepsis]].<ref name="Thomas 2012">{{cite journal|date=October 2014|title=Nociceptin system as a target in sepsis?|journal=Journal of Anesthesia|volume=28|issue=5|pages=759–67|doi=10.1007/s00540-014-1818-6|pmid=24728719|vauthors=Thomas R, Stover C, Lambert DG, Thompson JP|hdl=2381/33008|s2cid=11544831|url=https://figshare.com/articles/journal_contribution/10139792 |hdl-access=free}}</ref> 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.<ref>{{cite journal|date=June 2008|title=Nociceptin and urotensin-II concentrations in critically ill patients with sepsis|journal=British Journal of Anaesthesia|volume=100|issue=6|pages=810–4|doi=10.1093/bja/aen093|pmid=18430746|vauthors=Williams JP, Thompson JP, Young SP, Gold SJ, McDonald J, Rowbotham DJ, Lambert DG|doi-access=free}}</ref>

=== 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.<ref name=":0" />

== See also ==

* [[Nociceptor]]

== References ==

{{Reflist}}

== External links ==

{{Opioidergics}}

[[Category:Neuropeptides]]

[[Category:Opioid peptides]]

[[Category:Nociceptin receptor agonists]]

[[Category:Opioids]]