Neuropeptide FF (NPFF)
An endogenous RFamide peptide that opposes opioids — tied to morphine tolerance — and tunes pain, autonomic function and feeding. A research peptide, not a drug
Neuropeptide FF (NPFF) is an endogenous eight-amino-acid peptide of the brain and spinal cord, named for the phenylalanine (F) residues at each end of its sequence. It belongs to the RFamide family — peptides that end in arginine-phenylalanine-amide — and it is best known as an ‘anti-opioid’ peptide: it opposes the acute effects of opioids such as morphine, and a rise in its brain levels is linked to the development of opioid tolerance and dependence. Its effect on pain is route-dependent, blunting morphine analgesia when given into the brain’s ventricles but prolonging analgesia when given into the spinal fluid. Beyond opioids it regulates blood pressure and autonomic function, neuroendocrine hormone release, and — a more recent focus — feeding and energy balance. It signals through its own receptors, NPFFR1 and NPFFR2. NPFF is studied as a research tool and a lead for opioid and pain biology; it is not an approved medicine and has not been given to people as a treatment.
No established human dose Details ↓
Recommended Dosing
No established human dose
Neuropeptide FF is an endogenous human peptide that has never been given to people as a treatment. The human evidence is its presence in brain, spinal cord and plasma; the functional studies are in animals and cells, where it is injected into the brain or spinal fluid at experimental amounts that do not carry over to people.
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What is it?
Neuropeptide FF was isolated from bovine brain in the 1980s and characterized as a morphine-modulating, or ‘anti-opioid’, peptide. It is an eight-amino-acid RFamide (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide), cut from a precursor protein — pro-NPFF-A — that also yields a longer relative, neuropeptide AF (NPAF). The peptide is concentrated in the posterior pituitary, hypothalamus, medulla and the dorsal horn of the spinal cord, and it has even been detected in human plasma, hinting at a hormonal role.
Its defining property is its relationship with opioids. NPFF opposes the acute effects of morphine: injected into the brain’s ventricles it lowers the pain threshold and reverses morphine analgesia, and immuno-neutralizing it (mopping it up with antibodies) increases opioid analgesia. Levels of NPFF rise in the cerebrospinal fluid as opioid tolerance develops, and giving it can precipitate a withdrawal-like syndrome in morphine-tolerant animals — which is why it is studied as a participant in tolerance and dependence.
NPFF’s effect on pain is not simply ‘pro-pain’, though. Where it is applied matters: given into the spinal fluid, NPFF analogs produce a long-lasting, opioid-dependent analgesia and can potentiate morphine, while given above the spinal cord they oppose it. NPFF also dampens the rewarding effect of morphine (but not of alcohol) in animal models, consistent with an anti-opioid character.
The peptide reaches well beyond opioids. Through its receptors it controls autonomic and cardiovascular function — central injection can raise blood pressure and it regulates the neurosecretory cells that release vasopressin and oxytocin — lowers cortical excitability (an anticonvulsant-like effect shared with other RFamides), and, in a more recent line of work, helps control feeding and energy homeostasis, making its receptors a target of interest for obesity and appetite disorders.
Neuropeptide FF is an endogenous human peptide and a research tool, not a medicine. No published study has given NPFF to people as a treatment — the human side is its presence in brain, spinal cord and plasma, and the functional work is in animals and cells — it is approved nowhere, and material sold online as ‘neuropeptide FF’ or ‘NPFF’ is an unregulated research chemical. Nothing here is a dose or a therapy; this page records what the published science says about the peptide.
Mechanism of Action
Neuropeptide FF is an RFamide peptide that signals through the receptors NPFFR1 (GPR147) and NPFFR2 (GPR74). It opposes opioids, modulates pain by route, controls autonomic and neuroendocrine function, and helps regulate feeding and energy balance.
Anti-opioid modulation
NPFF opposes the acute effects of morphine and is linked to opioid tolerance and dependence: supraspinal NPFF reverses morphine analgesia and reduces morphine reward (PMIDs 9593588, 17884254), while spinal NPFF analogs give opioid-dependent analgesia.
NPFF receptor signalling
Through NPFFR1 (GPR147) and NPFFR2 (GPR74), NPFF couples to Gi/o proteins and lowers cAMP (PMID 16490283); in the hypothalamus it increases GABAergic inhibition of vasopressin/oxytocin neurons (PMID 16517015).
Autonomic, neuroendocrine and feeding
NPFF influences blood pressure and autonomic function and lowers cortical excitability, and a newer line of work places it in the control of feeding and energy homeostasis — central NPFF suppresses food intake (PMIDs 23291266, 34534716).
Published Research
These are studies of neuropeptide FF read from their PubMed abstracts on November 6, 2026. They include two reviews — one on NPFF in pain and analgesia, one on NPFF/NPVF distribution and energy homeostasis — an animal study of NPFF reducing morphine reward, an animal study of its effect on food intake, a cell study of its NPFF1 receptor signalling, and a brain-slice study of how it controls hypothalamic neurosecretory cells. Neuropeptide FF has not been given to people as a treatment in any published study; the human evidence is its presence in brain, spinal cord and plasma.
Neuropeptide FF, pain and analgesia
A review of NPFF (and neuropeptide AF) as anti-opioid peptides. Injected above the spinal cord, NPFF lowers the pain threshold and reverses morphine analgesia, and immuno-neutralizing it increases opioid analgesia; injected into the spinal fluid, NPFF analogs instead give long-lasting, opioid-dependent analgesia and potentiate morphine. The review frames NPFF as a neuromodulatory system interacting with opioids in the control of pain transmission.
NPFF/NPVF distribution and energy homeostasis
A review of neuropeptide FF and the related neuropeptide VF (NPVF), both RFamide peptides signalling through NPFFR1 and NPFFR2. Alongside their established roles in nociception, locomotion, reproduction and stress, the review highlights a newer major role in the control of energy homeostasis and food intake, and surveys where the peptides and receptors sit in central and peripheral tissues — framing the system as a possible target in obesity or anorexia.
NPFF reduces morphine reward in rats
Given into the brain of rats, neuropeptide FF inhibited the expression of morphine-induced conditioned place preference (a measure of drug reward) but not that of ethanol, and on its own produced neither preference nor clear aversion, fear behaviour or changes in locomotion. The result supports NPFF’s anti-opioid character and a role in morphine reward (a preclinical result).
NPFF signalling and food intake in mice
Centrally injected NPFF significantly lowered food intake in fasted mice. The study also found that RF9, a compound widely used as an NPFF-receptor antagonist, did not reverse NPFF’s anorectic effect and itself reduced food intake — casting doubt on RF9 as a clean antagonist while confirming NPFF’s suppression of feeding (a preclinical result).
How the NPFF1 receptor signals
In a cell line stably expressing the rat NPFF1 receptor, NPFF (and the related FMRFamide) coupled the receptor to a Gi/o protein and inhibited adenylyl cyclase (lowering cAMP), without engaging the MAPK or PI3K/Akt pathways. A ‘super-agonist’ analog over-activating the receptors produced effects in animals different from NPFF itself — detailing the receptor’s signalling machinery (a cell-based result).
NPFF controls hypothalamic neurosecretory cells
In rat brain slices, neuropeptide FF increased inhibitory (GABAergic) input onto the magnocellular neurosecretory cells of the hypothalamic paraventricular nucleus — the cells that release vasopressin and oxytocin — acting on neighbouring GABA neurons. This gave a cellular and anatomical basis for NPFF’s reported inhibition of vasopressin release in response to volume and osmotic challenges (an electrophysiology result in animal tissue).
No Established Human Dose
Neuropeptide FF is an endogenous human peptide that has never been given to people as a treatment. The human evidence is its presence in brain, spinal cord and plasma; the functional studies are in animals and cells, where it is injected into the brain or spinal fluid at experimental amounts that do not carry over to people. No regulator has approved any dose, and no published human dose exists, so no amount is printed here.
What this rests on: PMID 9593588, PMID 17884254, PMID 23291266.
Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, 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 Neuropeptide FF (NPFF) is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
Unknown: no human dose of Neuropeptide FF (NPFF) has been established (see No Established Human Dose below), so there is no amount to work out. The reconstitution calculator does the arithmetic for any vial, water and dose.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Neuropeptide FF (NPFF), 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 Neuropeptide FF (NPFF) stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking Neuropeptide FF (NPFF). What the human studies gave and how is set out under No Established Human Dose.
What to expect, and when
How long it stays in the body: a half-life of not established for humans as a drug; an endogenous signalling peptide. After about five half-lives almost none is left.
When effects appear: unknown; no source on this page gives a time to effect for Neuropeptide FF (NPFF). Results reported in the studies are under Published Research.
Source: half-life: PMID 9593588.
Side effects, and when to stop or get help
From the Side Effects section: No human adverse-event data exist: no published study has administered neuropeptide FF to people; In animals, central NPFF opposes opioid analgesia and can precipitate a withdrawal-like syndrome in morphine-tolerant rats (PMID 9593588) — an anti-opioid action, not a safety profile; Central NPFF can raise blood pressure and alter autonomic function (PMID 16517015), so systemic effects would be expected if it were administered; Material sold online as ‘neuropeptide FF’ or ‘NPFF’ is an unregulated research chemical of unverified content. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Neuropeptide FF (NPFF). Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“Neuropeptide FF is an endogenous peptide that has not been given to people as a drug, so there is no human safety profile; the points below reflect that research status”).
Interactions
Unknown: a PubMed search for human interaction studies of Neuropeptide FF (NPFF) (reviewed 2026-11-06) 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 Neuropeptide FF (NPFF) 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. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a drug: Drugs@FDA and the openFDA label endpoint hold no record, and FDA GSRS and ChEMBL hold no substance record for neuropeptide FF (searched November 6, 2026)). Sport: Not on the 2026 List.
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
Neuropeptide FF is an endogenous peptide that has not been given to people as a drug, so there is no human safety profile; the points below reflect that research status.
Contraindications & Cautions
Neuropeptide FF has no approved use and no label. These points reflect its endogenous, research status.
Legal Status
Neuropeptide FF is an endogenous human peptide studied as a research compound; it is not a drug and is not approved in any country.
Frequently Asked Questions
?What is neuropeptide FF?
An endogenous human peptide — an eight-amino-acid RFamide (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide) of the brain and spinal cord. Cut from the same precursor as neuropeptide AF, it signals through the receptors NPFFR1 (GPR147) and NPFFR2 (GPR74) and is best known as an ‘anti-opioid’ peptide.
?What does it do?
It opposes the effects of opioids such as morphine and is linked to opioid tolerance (PMID 9593588), modulates pain by route, reduces morphine reward (PMID 17884254), controls autonomic and neuroendocrine function (PMID 16517015) and helps regulate feeding (PMIDs 23291266, 34534716).
?Is it a treatment for anything?
No. Neuropeptide FF is a research peptide used to study opioid, pain and feeding biology; its receptors are potential drug targets. No human trial has administered it, and it is approved nowhere.
?Is it approved or available to buy?
No. Neuropeptide FF is not a medicine, has no FDA application or label, and is approved nowhere. Material sold online as neuropeptide FF or NPFF is an unregulated research chemical. Grey Peptides lists no sellers and recommends no source; this page records the published science.
References
- [review] Roumy M, et al. "Neuropeptide FF, pain and analgesia." Eur J Pharmacol, 1998;345(1):1-11. PMID: 9593588.
- [review] Koller J, et al. "The distribution of Neuropeptide FF and Neuropeptide VF in central and peripheral tissues and their role in energy homeostasis control." Neuropeptides, 2021;90:102198. PMID: 34534716.
- [animal] Kotlinska J, et al. "Neuropeptide FF (NPFF) reduces the expression of morphine- but not of ethanol-induced conditioned place preference in rats." Peptides, 2007;28(11):2235-42. PMID: 17884254.
- [animal] Maletínská L, et al. "Neuropeptide FF analog RF9 is not an antagonist of NPFF receptor and decreases food intake in mice after its central and peripheral administration." Brain Res, 2013;1498:33-40. PMID: 23291266.
- [mechanism] Chen JC, et al. "Rat NPFF(1) receptor-mediated signaling: functional comparison of neuropeptide FF (NPFF), FMRFamide and PFR(Tic)amide." Peptides, 2006;27(5):1005-14. PMID: 16490283.
- [mechanism] Jhamandas JH, et al. "Neuropeptide FF (NPFF) control of magnocellular neurosecretory cells of the rat hypothalamic paraventricular nucleus (PVN)." Peptides, 2006;27(5):973-9. PMID: 16517015.
- [other] UniProt O15130 (NPFF_HUMAN), read November 6, 2026: neuropeptide FF is a product of the NPFF gene (neuropeptide FF-amide peptide precursor), the same precursor that yields neuropeptide AF (NPAF); it signals through the G-protein-coupled receptors NPFFR1 (GPR147) and NPFFR2 (GPR74). https://www.uniprot.org/uniprotkb/O15130/entry
- [other] Neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide) and the longer neuropeptide AF were isolated from bovine brain and first characterized as anti-opioid peptides of the RFamide family; the biology is set out in the pain-and-analgesia review carded on this page (read November 6, 2026).
- [other] US FDA, Drugs@FDA and the drug label endpoint (openFDA), searched November 6, 2026: no application and no label record for neuropeptide FF. It is an endogenous human peptide, not a registered drug; FDA GSRS and ChEMBL hold no substance record for it.
Sources & Citations
The six studies carded above were read from their PubMed records on November 6, 2026. Identity comes from UniProt (O15130, gene NPFF); neuropeptide FF’s RFamide octapeptide sequence, its origin alongside neuropeptide AF, its NPFFR1/NPFFR2 (GPR147/GPR74) receptors and its anti-opioid, autonomic, neuroendocrine and feeding roles are from the reviews and studies carded here; the absence of US approval and of a drug substance record from Drugs@FDA, openFDA, FDA GSRS and ChEMBL was checked 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.