Nociceptin
The fourth member of the opioid peptide family, found in 1995, measured in many diseases and given to people only as a bladder instillation
Nociceptin, also called orphanin FQ or N/OFQ, is a 17-amino-acid peptide the body makes from the precursor prepronociceptin. It switches on the NOP receptor, a relative of the mu, delta and kappa opioid receptors that ignores the classic opioids. In animals it can block or worsen pain depending on where it acts. In people it has mostly been measured in blood and spinal fluid; the only times it was given were small trials that put it into the bladder of patients with overactive bladder from spinal cord disease. Drugs aimed at its receptor are separate molecules.
Used in human trials: 1 mg in 10 mL saline, Once daily, at the first morning catheterisation, Intravesical (Trial: neurogenic overactive bladder, 18 patients (randomised, plac...) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
Nociceptin was found in 1995 by two groups working backwards from a receptor. Gene sequencing had turned up a receptor that looked like the opioid receptors but responded to no known opioid, a so-called orphan receptor. One group isolated a 17-amino-acid peptide that switched it on, traced it to a rat brain gene and named it nociceptin, because injected into the brains of mice it made them more sensitive to pain. Another group found the same peptide in pig brain and called it orphanin FQ, after the orphan receptor and its first and last amino acids, phenylalanine and glutamine. The receptor is now called NOP.
Its sequence starts like the opioid peptides, but the differences matter. Nociceptin does not act on the mu, delta or kappa receptors that morphine and the endorphins use, and on human airway tissue the opioid blocker naloxone did not stop its action. Where it acts decides what it does. Injected into the brain of mice it lowered pain thresholds, while injected into the spinal canal it relieved pain. In monkeys, injected near the brainstem, it relieved pain without the itch that morphine caused. Knockout mice lacking the peptide were slower to develop experimental epilepsy.
Most human studies measure it. Nociceptin is present in human cerebrospinal fluid at several times its blood level, and mass spectrometry has confirmed the mature peptide in human brain and spinal fluid. Blood levels, measured by radioimmunoassay or ELISA, were lower in migraine, fibromyalgia and chronic ischaemic heart and leg artery disease, and higher after bouts of unstable angina, in sepsis, after heart surgery and in liver disease. Spinal fluid levels were about three and a half times higher in Parkinson's disease than in other neurological patients. One study reported a tenfold rise in liver cancer, but a later study found it did not separate liver cancer from cirrhosis and called it useless as a cancer marker. These are mostly small, single-centre studies, and none shows that the peptide causes the disease.
The one place nociceptin itself has been given to people is the bladder. In rats it calms the reflex that empties the bladder by quietening sensory nerves. Urologists then filled the bladders of patients with neurogenic detrusor overactivity, an overactive bladder caused by spinal cord injury or other nerve disease, with a dilute nociceptin solution. In a pilot study and a small double-blind trial against an inactive analogue, bladder capacity and the volume at which the bladder started to contract both rose, while healthy volunteers showed no change. In a ten-day randomised trial in 18 patients who emptied their bladders by catheter, a daily morning instillation of nociceptin more than halved leaking episodes, while placebo did not. These trials were tiny and were never followed by a licensed product.
Most drug development has moved to other molecules. Chemists have built modified peptide analogues and non-peptide compounds that switch the receptor on or block it, and mixed drugs such as cebranopadol act on both the NOP and mu receptors. Monkey studies suggest such drugs may relieve pain with less abuse potential and breathing depression than standard opioids. Those are separate molecules; the reviews that describe them are listed under References, and their results do not belong to nociceptin.
Nociceptin is not an approved medicine anywhere. The only human amounts on record are the bladder instillations above, given under specialist supervision; nothing is known about injecting it into the body, and it is broken down in blood.
Mechanism of Action
Nociceptin acts on the NOP receptor, an opioid-like receptor that dampens nerve-cell activity; it does not use the mu, delta or kappa receptors.
NOP receptor signalling
Binding NOP lowers cyclic AMP and opens potassium channels, making nerve cells less excitable and reducing the release of transmitters such as acetylcholine.
Pain: depends on where
In mice it increased pain sensitivity when injected into the brain, but relieves pain when acting in the spinal cord or, in monkeys, near the brainstem.
Bladder reflex
In the bladder it quietens sensory nerves that trigger emptying, which is why it was tried in nerve-related overactive bladder.
Published Research
These are studies of nociceptin itself, read from their PubMed abstracts: three bladder instillation trials, measurements in human blood, spinal fluid and brain, laboratory studies on human tissue and blood, animal studies, and two reviews. Reviews of synthetic receptor drugs are listed under References.
Pilot: nociceptin in the overactive bladder
Five healthy volunteers and nine patients with nerve-related bladder overactivity that resisted standard therapy had their bladders filled with a dilute nociceptin solution. Volunteers showed no change; in patients, capacity rose from 164 to 301 mL and the volume that set off contractions from 93 to 231 mL. The effect had gone by a 15-day check, and no severe symptoms were reported.
Double-blind bladder study against an inactive analogue
Fourteen patients with overactive bladder after spinal cord injury were randomised to nociceptin or an inactive analogue as the control. Nociceptin raised bladder capacity from 139 to 240 mL and the trigger volume for contractions from 84 to 201 mL; the fall in maximal pressure was not significant, and the control did nothing.
Ten days of daily bladder instillation
In 18 patients using self-catheterisation for neurogenic incontinence, daily nociceptin instillation for 10 days cut leaks from 2.18 to 0.94 a day and raised diary bladder capacity from 171 to 294 mL, while saline did neither. All patients completed the study, with no significant side effects reported.
First measurement in human spinal fluid
In 20 women at Caesarean section or in labour, nociceptin was found in every spinal fluid sample at around 50 to 65 pg/mL, much higher than in plasma, where it was detectable in 16 of 20. Levels did not differ between women in labour pain and those having planned surgery.
Mass spectrometry confirms the mature peptide
Using affinity purification, HPLC and mass spectrometry, the authors identified mature nociceptin and its sibling peptide nocistatin in human brain tissue and spinal fluid, and found two forms of nocistatin.
Lower in migraine
Eighteen people with migraine without aura had lower plasma nociceptin between attacks than 24 controls (5.8 vs 9.7 pg/mL), and lower still in six measured early in an attack; lower levels went with more frequent attacks.
Lower in fibromyalgia
Women with fibromyalgia had lower plasma nociceptin than matched controls, with the clearest difference in the luteal phase of the menstrual cycle, suggesting links with sex hormones and the stress system.
Higher after episodes of unstable angina
Forty-one patients with recent spontaneous chest-pain episodes had higher plasma nociceptin than 20 matched controls (15.2 vs 8.5 pg/mL). Brief, painless ischaemia induced with adenosine during a heart scan did not change it, pointing to the pain rather than the ischaemia.
Lower in chronic artery disease
In a pilot study, plasma nociceptin was lower in patients with severe stable angina than in those with milder angina and in healthy controls, and lower in peripheral artery disease than in controls.
Raised in sepsis and after heart surgery
In 82 intensive-care patients with sepsis, plasma nociceptin rose on the first two days compared with their own recovery samples, while white-cell expression of its precursor and receptor fell. Similar but smaller and shorter changes followed cardiopulmonary bypass in 40 patients.
Higher in Parkinson's disease spinal fluid
Spinal fluid from people with Parkinson's disease having deep brain stimulation surgery held about 3.5 times more nociceptin (148 vs 41 fmol/mL) than that of other neurological patients. In rats, dopamine loss raised nociceptin production in the substantia nigra.
A reported tenfold rise in liver cancer
By radioimmunoassay, plasma nociceptin was modestly raised in Wilson disease, primary biliary cirrhosis and cirrhosis, and about ten times higher in 29 patients with hepatocellular carcinoma than in healthy controls, with or without pain.
Not a useful liver cancer marker after all
Measured by ELISA in 28 liver cancer patients, 30 with cirrhosis and 25 controls, nociceptin was raised in chronic liver disease whether or not cancer was present and did worse than alpha-fetoprotein; the authors concluded it does not help diagnose liver cancer.
Relaxes nerve-driven contraction of human airways
In bronchial strips from 23 lung-surgery patients, nociceptin reduced nerve-triggered cholinergic contractions by a modest 11.5% at most. Naloxone did not stop it, a selective NOP blocker did, and the effect seemed to run through potassium channels.
How human blood breaks it down
Incubated in fresh human blood and tracked by mass spectrometry, nociceptin was cut mainly between its first two amino acids, giving nociceptin (2-17), with minor cuts at basic residues; it lasted longer than dynorphin A (1-17) under the same conditions.
Discovery as orphanin FQ
A 17-amino-acid peptide purified from pig brain activated the orphan receptor LC132 at nanomolar levels and bound it with high affinity but did not activate opioid receptors. Injected into mouse brain it reduced movement, gave no pain relief on the hot plate and increased pain sensitivity in the tail-flick test.
Pain relief when given in the spine
Given into the spinal canal of mice, nociceptin produced quick, dose-dependent pain relief without the hyperalgesia seen after brain injection; two shorter fragments worked far more weakly.
Pain relief without itch in monkeys
In awake rhesus monkeys, nociceptin injected near the brainstem relieved pain through NOP receptors and did not cause scratching, unlike morphine given the same way, which caused head scratching.
Mice without the peptide resist epilepsy
Mice lacking the nociceptin gene needed more stimulations and longer seizures to become kindled than their normal littermates, suggesting the peptide helps epilepsy develop in this model.
The orphanin FQ/nociceptin system
A chapter describing nociceptin as the first neuropeptide discovered by searching for the natural ligand of an orphan receptor, its sequence likeness to opioid peptides, and its roles across the body.
Nociceptin and the urinary bladder
The chapter summarises how nociceptin quietens the rat voiding reflex through sensory fibres, the human bladder instillation results in overactive bladder, and the development of a longer-acting modified peptide agonist for the same purpose.
Dosing Data
Nociceptin is not approved anywhere as a medicine. These are the amounts from the published human bladder studies carded above, as their abstracts state them; none is a licensed dose.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Nociceptin is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
No worked example: none of the doses on this page is a fixed amount in mg or mcg injected under the skin or into a muscle (the routes given are: intravesical). There is no home-mixing step to show. The reconstitution calculator does the arithmetic for any vial.
Source: the route and amount of each dose row in Dosing Data below.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Nociceptin, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Nociceptin stays intact once mixed.
How it is taken
As it was given in human studies: Intravesical (Once daily, at the first morning catheterisation; Trial: neurogenic overactive bladder, 18 patients (randomised, placebo-controlled)).
For injection technique, sites and needle disposal, see the mixing guide.
Source: Used in human trials: the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: not established by a measurement cited on this entry.
How long the doses were given: Trial: neurogenic overactive bladder, 18 patients (randomised, placebo-controlled): 10 days; Study: overactive bladder after spinal cord injury, 14 patients (double-blind): One session; Pilot: 9 patients and 5 healthy volunteers: One session.
When effects appear: unknown; no source on this page gives a time to effect for Nociceptin. Results reported in the studies are under Published Research.
Source: Used in human trials, the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: No severe symptoms in the pilot study (PMID 11696742); No significant side effects or problems with the procedure over 10 days of daily instillation (PMID 17070267); No data at all on nociceptin injected into a vein, muscle or under the skin in people. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Nociceptin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“From the three small bladder studies above, which gave nociceptin only into the bladder”).
Interactions
Unknown: a PubMed search for human interaction studies of Nociceptin (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Nociceptin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Nociceptin's expected mass, 1,809.1 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a medicine: an endogenous neuropeptide). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
From the three small bladder studies above, which gave nociceptin only into the bladder.
Contraindications & Cautions
No product label exists. These cautions follow from the evidence.
Legal Status
Nociceptin is a research neuropeptide; it is not approved as a medicine anywhere in the sources read.
Frequently Asked Questions
?What is nociceptin?
A 17-amino-acid neuropeptide, also called orphanin FQ, that the body makes from prepronociceptin. It is the natural ligand of the NOP receptor, the fourth member of the opioid receptor family.
?Is nociceptin an opioid?
It is related in sequence and its receptor is opioid-like, but it does not act on the mu, delta or kappa receptors that morphine uses.
?Does nociceptin relieve pain?
It depends where it acts. In rodents, injected into the brain it increased pain sensitivity, while injected into the spinal canal it relieved pain. In monkeys, near the brainstem, it relieved pain without itch.
?Has nociceptin been given to people?
Only into the bladder. Small trials put it into the bladders of patients with nerve-related overactive bladder; capacity rose and leaks fell over 10 days, with no significant side effects reported.
?What do blood levels of nociceptin mean?
Small studies found lower levels in migraine, fibromyalgia and chronic artery disease and higher levels in sepsis, after angina attacks and in liver disease. None makes it a diagnostic test.
?What about drugs that act on its receptor?
Synthetic agonists and blockers of the NOP receptor, including cebranopadol, are separate molecules. Their trials are not results for nociceptin.
References
- [clinical-trial] Lazzeri M, et al. "Urodynamic and clinical evidence of acute inhibitory effects of intravesical nociceptin/orphanin FQ on detrusor overactivity in humans: a pilot study." J Urol, 2001;166(6):2237-40. PMID: 11696742.
- [clinical-trial] Lazzeri M, et al. "Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor overactivity: a randomized, placebo-controlled, double-blind study." Urology, 2003;61(5):946-50. PMID: 12736013.
- [clinical-trial] Lazzeri M, et al. "Daily intravesical instillation of 1 mg nociceptin/orphanin FQ for the control of neurogenic detrusor overactivity: a multicenter, placebo controlled, randomized exploratory study." J Urol, 2006;176(5):2098-102. PMID: 17070267.
- [pubmed] Brooks H, et al. "Identification of nociceptin in human cerebrospinal fluid: comparison of levels in pain and non-pain states." Pain, 1998;78(1):71-73. PMID: 9822213.
- [pubmed] Joseph T, et al. "Identification of mature nocistatin and nociceptin in human brain and cerebrospinal fluid by mass spectrometry combined with affinity chromatography and HPLC." Peptides, 2006;27(1):122-30. PMID: 16043263.
- [pubmed] Ertsey C, et al. "Plasma nociceptin levels are reduced in migraine without aura." Cephalalgia, 2005;25(4):261-6. PMID: 15773823.
- [pubmed] Anderberg UM, et al. "Plasma levels on nociceptin in female fibromyalgia syndrome patients." Z Rheumatol, 1998;57 Suppl 2:77-80. PMID: 10025089.
- [pubmed] Fontana F, et al. "Plasma nociceptin/orphanin FQ levels rise after spontaneous episodes of angina, but not during induced myocardial ischemia." Peptides, 2009;30(9):1705-9. PMID: 19560501.
- [pubmed] Krepuska M, et al. "Plasma nociceptin/orphanin FQ levels are lower in patients with chronic ischemic cardiovascular diseases--A pilot study." Regul Pept, 2011;169(1-3):1-5. PMID: 21310194.
- [pubmed] Thompson JP, et al. "The Nociceptin/Orphanin FQ system is modulated in patients admitted to ICU with sepsis and after cardiopulmonary bypass." PLoS One, 2013;8(10):e76682. PMID: 24124588.
- [pubmed] Marti M, et al. "Brain interstitial nociceptin/orphanin FQ levels are elevated in Parkinson's disease." Mov Disord, 2010;25(11):1723-32. PMID: 20589874.
- [pubmed] Szalay F, et al. "Increased nociceptin/orphanin FQ plasma levels in hepatocellular carcinoma." World J Gastroenterol, 2004;10(1):42-5. PMID: 14695766.
- [pubmed] Spadaro A, et al. "Low utility of plasma Nociceptin/orphanin FQ in the diagnosis of hepatocellular carcinoma." World J Gastroenterol, 2006;12(29):4716-20. PMID: 16937445.
- [pubmed] Basso M, et al. "Nociceptin/orphanin FQ inhibits electrically induced contractions of the human bronchus via NOP receptor activation." Peptides, 2005;26(8):1492-6. PMID: 16042989.
- [pubmed] Yu J, et al. "Nociceptin in vitro biotransformation in human blood." Peptides, 1996;17(5):873-6. PMID: 8844779.
- [pubmed] Reinscheid RK, et al. "Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor." Science, 1995;270(5237):792-4. PMID: 7481766.
- [pubmed] King MA, et al. "Spinal analgesic activity of orphanin FQ/nociceptin and its fragments." Neurosci Lett, 1997;223(2):113-6. PMID: 9089686.
- [pubmed] Ding H, et al. "Supraspinal actions of nociceptin/orphanin FQ, morphine and substance P in regulating pain and itch in non-human primates." Br J Pharmacol, 2015;172(13):3302-12. PMID: 25752320.
- [pubmed] Binaschi A, et al. "Delayed epileptogenesis in nociceptin/orphanin FQ-deficient mice." Neuroreport, 2003;14(6):825-7. PMID: 12858040.
- [review] Civelli O. "The orphanin FQ/nociceptin (OFQ/N) system." Results Probl Cell Differ, 2008;46:1-25. PMID: 18193175.
- [review] Angelico P, et al. "Nociceptin/Orphanin FQ and Urinary Bladder." Handb Exp Pharmacol, 2019;254:347-365. PMID: 30430260.
- [pubmed] Meunier JC, et al. "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor." Nature, 1995;377(6549):532-5. PMID: 7566152.
- [review] Wtorek K, et al. "Potential of Nociceptin/Orphanin FQ Peptide Analogs for Drug Development." Chem Biodivers, 2021;18(1):e2000871. PMID: 33351271.
- [review] Ding H, et al. "Nociceptin Receptor-Related Agonists as Safe and Non-addictive Analgesics." Drugs, 2023;83(9):771-793. PMID: 37209211.
- [other] UniProt Q13519: prepronociceptin, Homo sapiens; nociceptin is peptide 130 to 146, FGGFTGARKSARKLANQ. Read October 28, 2026. https://www.uniprot.org/uniprotkb/Q13519/entry
Sources & Citations
Every study on this page was read from its PubMed record on October 28, 2026. Regulatory status comes from Drugs@FDA (openFDA) and the EMA medicines list, and trial status from ClinicalTrials.gov, read the same day. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.