Neuropeptides: Complete Category Overview

In 1931, Ulf von Euler and John Gaddum isolated something unusual from horse brain and intestine. The substance caused smooth muscle to contract and blood pressure to drop, but it was not any known neurotransmitter. They called it "Substance P" — the P standing for "powder" or "preparation," depending on which account you read. It would take four decades before its amino acid sequence was determined, and several more before scientists grasped the enormous family of signaling molecules it represented.

Today, researchers have identified over 100 neuropeptides in the mammalian nervous system, with the NeuroPep 2.0 database cataloging 5,949 non-redundant neuropeptide entries across 493 organisms and 65 neuropeptide families (Wang et al., 2023). These molecules regulate nearly every brain function you can name — pain perception, mood, appetite, sleep, memory, social bonding, stress responses, and reward. They also represent one of the most promising but challenging frontiers in drug development.

This guide covers what neuropeptides are, how they differ from classical neurotransmitters, the major families you should know, and where therapeutic development stands.

What Makes a Neuropeptide
How Neuropeptides Differ from Classical Neurotransmitters
Major Neuropeptide Families
Opioid Peptides
Tachykinins
Hypothalamic Releasing and Inhibiting Hormones
Orexins and Sleep Regulation
Oxytocin and Vasopressin
Neuropeptide Y Family
Other Families of Note
Neuropeptides in Brain Function
Therapeutic Applications and Drug Development
Research Challenges and Future Directions
FAQ
The Bottom Line
References

What Makes a Neuropeptide {#what-makes-a-neuropeptide}

Neuropeptides are small proteins — typically 3 to 100 amino acids long — produced by neurons and used for cell-to-cell signaling in the nervous system. They function as neurotransmitters, neuromodulators, or neurohormones, depending on how and where they act.

What distinguishes neuropeptides from other signaling molecules is their biology. They are synthesized as larger precursor proteins (prepropeptides) in the cell body, then processed through enzymatic cleavage and post-translational modifications as they travel down the axon in dense-core vesicles. This synthesis-and-transport process takes hours, compared to the milliseconds needed to synthesize small-molecule neurotransmitters like glutamate or GABA at the synapse.

The precursor system also means that a single gene can produce multiple active neuropeptides. The pro-opiomelanocortin (POMC) gene, for instance, yields beta-endorphin, ACTH, and several forms of melanocyte-stimulating hormone (MSH) — all from one precursor protein. This "one gene, many peptides" principle is common throughout the neuropeptide world.

For a broader context on peptide biology, see our beginner's guide to peptides and peptide classifications guide.

How Neuropeptides Differ from Classical Neurotransmitters {#how-neuropeptides-differ-from-classical-neurotransmitters}

Neuropeptides and classical neurotransmitters (like serotonin, dopamine, glutamate, and GABA) both carry signals between neurons, but they operate by different rules.

Feature	Classical Neurotransmitters	Neuropeptides
Size	Small molecules (<200 Da)	3-100 amino acids (300-10,000+ Da)
Synthesis	At the synapse, rapid	In cell body, slow (hours)
Storage	Small clear vesicles	Large dense-core vesicles
Release trigger	Low-frequency firing	High-frequency or burst firing
Action	Fast (milliseconds)	Slow (seconds to minutes)
Receptors	Ion channels or GPCRs	Almost exclusively GPCRs
Reuptake	Yes (transported back into neuron)	No (degraded by extracellular peptidases)
Effective distance	Synaptic cleft (nanometers)	Can diffuse micrometers to millimeters

The practical implication: classical neurotransmitters are the brain's fast digital signals — on/off, excitatory/inhibitory. Neuropeptides are more like the brain's analog dial, modulating the gain, sensitivity, and tone of neural circuits over longer timescales. A neuron might release glutamate for rapid signaling and co-release a neuropeptide that changes how the circuit responds for the next several minutes.

This modulating role explains why neuropeptide signaling is so relevant to mood, stress, appetite, and social behavior — processes that unfold over minutes to hours, not milliseconds.

Major Neuropeptide Families {#major-neuropeptide-families}

The neuropeptide world is organized into families based on shared precursor genes, structural similarities, or receptor relationships. Here are the families that matter most for understanding brain function and therapeutic development.

Opioid Peptides {#opioid-peptides}

The endogenous opioid system is probably the most extensively studied neuropeptide family — and the one with the most direct clinical relevance, given the centrality of opioid signaling to pain, addiction, and reward.

The Four Subfamilies

More than 20 opioid peptides have been identified, falling into four groups based on their precursor genes (Bagley & Bhatt, 2019):

Endorphins derive from the POMC gene. Beta-endorphin is the most potent and best-characterized — a 31-amino-acid peptide released by the pituitary and hypothalamus. It binds preferentially to mu-opioid receptors and is a major player in stress-induced analgesia, exercise-induced euphoria (the "runner's high"), and reward circuits. Alpha- and gamma-endorphin are shorter fragments with distinct but less-studied activities.

Enkephalins were discovered in 1975 by John Hughes and Hans Kosterlitz, becoming the first endogenous opioid peptides identified. Two forms exist: Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), both just five amino acids long. They derive from the proenkephalin (PENK) gene, which contains six copies of Met-enkephalin and one copy of Leu-enkephalin. Enkephalins act primarily at delta-opioid receptors and are involved in pain modulation, particularly in the spinal cord.

Dynorphins come from the prodynorphin (PDYN) gene and preferentially bind kappa-opioid receptors. Unlike the rewarding effects of mu-receptor activation, kappa-receptor signaling is associated with dysphoria and aversion — which is why dynorphin signaling is implicated in stress, anxiety, and the negative emotional states of addiction withdrawal. Dynorphin A (17 amino acids) and dynorphin B (13 amino acids) are the primary forms.

Nociceptin (also called orphanin FQ) derives from the PNOC gene and binds the nociceptin opioid receptor (NOP). It lacks the conserved Tyr-Gly-Gly-Phe motif shared by the other three families and was the last major opioid peptide family discovered (1995). Its role in pain modulation is complex — it can produce either analgesia or hyperalgesia depending on the brain region and dose.

Clinical Relevance

The opioid peptide system is the biological target of opioid analgesics (morphine, fentanyl, oxycodone) and opioid antagonists (naloxone, naltrexone). Understanding endogenous opioid signaling has been central to addiction research, pain management, and the development of abuse-deterrent formulations.

Tachykinins {#tachykinins}

The tachykinin family — named for their ability to rapidly contract gut smooth muscle — includes substance P, one of the first neuropeptides ever discovered. All tachykinins share a characteristic C-terminal sequence: Phe-X-Gly-Leu-Met-NH2, where X is either an aromatic or aliphatic amino acid (Severini et al., 2002).

Key Members

Substance P (11 amino acids) is the founding member, encoded by the TAC1 gene along with neurokinin A (NKA), neuropeptide K, and neuropeptide gamma. Substance P binds the NK1 receptor and is a major mediator of pain signaling (nociception), neurogenic inflammation, and the vomiting reflex. NK1 receptor antagonists like aprepitant (Emend) are approved anti-nausea drugs — a direct therapeutic product of tachykinin research.

Neurokinin A and Neurokinin B (NKB, encoded by the TAC3 gene) act through NK2 and NK3 receptors, respectively. NKB has drawn attention for its role in reproductive endocrinology — mutations in the NKB or NK3R genes cause hypogonadotropic hypogonadism, and NK3R antagonists are in clinical development for hot flashes and endometriosis.

Hemokinin-1, the newest family member (discovered 2000), is encoded by TAC4 and has immune-modulatory functions beyond the nervous system.

In total, at least eight named mammalian tachykinins have been identified.

Hypothalamic Releasing and Inhibiting Hormones {#hypothalamic-releasing-and-inhibiting-hormones}

The hypothalamus produces a set of neuropeptides that control the pituitary gland, which in turn regulates growth, reproduction, stress responses, thyroid function, and lactation. These "releasing hormones" and "inhibiting hormones" are the master regulators of the endocrine system.

Corticotropin-releasing hormone (CRH) is a 41-amino-acid peptide that triggers ACTH release from the pituitary, initiating the stress response cascade. CRH receptor antagonists have been extensively studied for depression and anxiety, though clinical success has been limited so far.

Gonadotropin-releasing hormone (GnRH) is a 10-amino-acid peptide controlling reproductive hormone release. GnRH analogs (leuprolide, goserelin, gonadorelin) are widely used clinically — for prostate cancer, endometriosis, precocious puberty, and fertility treatments. The GnRH system is covered in our gonadorelin profile.

Growth hormone-releasing hormone (GHRH) is a 44-amino-acid peptide that stimulates growth hormone secretion. Synthetic GHRH analogs like sermorelin, tesamorelin, and CJC-1295 are used or studied for growth hormone deficiency and age-related hormone decline.

Somatostatin (14 or 28 amino acids) inhibits growth hormone, insulin, and glucagon release. Synthetic analogs octreotide and lanreotide are approved for acromegaly and neuroendocrine tumors.

Thyrotropin-releasing hormone (TRH) is one of the smallest neuropeptides — just three amino acids (pGlu-His-Pro-NH2) — and controls thyroid function through TSH stimulation.

Orexins and Sleep Regulation {#orexins-and-sleep-regulation}

The orexin system (also called the hypocretin system) was discovered independently by two groups in 1998. It consists of just two peptides — orexin-A (33 amino acids) and orexin-B (28 amino acids) — produced by a small cluster of roughly 10,000-20,000 neurons in the lateral hypothalamus (de Lecea et al., 2006).

Despite this small neuronal population, the orexin system has outsized influence. These neurons project widely throughout the brain and spinal cord, regulating wakefulness, appetite, energy balance, reward seeking, and autonomic functions.

The clinical significance became clear with the discovery that type 1 narcolepsy — characterized by excessive daytime sleepiness and sudden muscle weakness (cataplexy) — is caused by selective destruction of orexin-producing neurons, likely through an autoimmune process. Patients with narcolepsy type 1 have undetectable orexin-A levels in their cerebrospinal fluid.

Therapeutic Applications

The orexin system has generated two classes of approved drugs:

Orexin receptor antagonists (suvorexant/Belsomra, lemborexant/Dayvigo) block orexin signaling to promote sleep. These were approved for insomnia and represent a conceptually different approach from older sleep medications — rather than broadly suppressing brain activity, they specifically counteract the arousal-promoting orexin signal.

Orexin receptor agonists are in development for narcolepsy, aiming to replace the missing orexin signal. This is a more targeted approach than current narcolepsy treatments (stimulants, sodium oxybate), which manage symptoms rather than addressing the underlying deficit.

Oxytocin and Vasopressin {#oxytocin-and-vasopressin}

Oxytocin and vasopressin (also called antidiuretic hormone, ADH) are closely related nine-amino-acid cyclic peptides that differ by just two residues. Despite this structural similarity, they serve strikingly different functions.

Oxytocin is best known for its roles in labor (uterine contraction), lactation (milk let-down), and social bonding. Research over the past two decades has expanded this picture considerably — oxytocin modulates trust, empathy, social recognition, pair bonding, and stress responses. Clinical trials have explored intranasal oxytocin for autism spectrum disorder, social anxiety, schizophrenia, and PTSD, with mixed but ongoing results.

Vasopressin primarily regulates water balance (acting on kidney collecting ducts to concentrate urine) and blood pressure (vasoconstriction). In the brain, vasopressin influences aggression, territorial behavior, and social memory. Desmopressin, a synthetic vasopressin analog, is widely used for diabetes insipidus and bedwetting.

Both peptides are synthesized in the hypothalamus (supraoptic and paraventricular nuclei) and released both into the bloodstream from the posterior pituitary and directly into brain circuits from axonal projections. This dual release — peripheral hormone and central neuromodulator — is a defining feature of these peptides.

Neuropeptide Y Family {#neuropeptide-y-family}

Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammalian brain. It belongs to a family that includes peptide YY (PYY) and pancreatic polypeptide (PP), all sharing a characteristic "PP-fold" tertiary structure and 36 amino acids.

NPY is a powerful appetite stimulant — injection of NPY into the hypothalamus produces intense feeding behavior in animals. It also modulates anxiety, stress resilience, circadian rhythms, blood pressure, and seizure threshold. Interestingly, high NPY levels are associated with stress resilience in military personnel, suggesting a protective role against PTSD.

Peptide YY is released from gut endocrine cells after eating and suppresses appetite — functioning as a satiety signal. PYY analogs are being studied for obesity treatment.

Pancreatic polypeptide is released after meals and helps regulate pancreatic secretion and gastric motility.

The NPY family acts through Y1-Y5 receptors, all G-protein-coupled. The diversity of receptor subtypes and their distribution across different brain regions explains how a single peptide family can influence such varied functions.

Other Families of Note {#other-families-of-note}

Several additional neuropeptide families are worth knowing:

Galanin (29-30 amino acids) modulates pain, feeding, mood, and cognition. It is co-expressed with classical neurotransmitters in many brain regions and typically acts as an inhibitory modulator. Galanin receptor signaling is being explored in epilepsy and Alzheimer's research.

Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide and the most potent known vasodilator. CGRP's role in migraine has led to a new drug class — CGRP antagonists (erenumab, fremanezumab, galcanezumab) are now first-line migraine preventives, representing one of the biggest neuropeptide therapeutic success stories of the past decade.

Vasoactive intestinal peptide (VIP) is a 28-amino-acid peptide involved in circadian rhythms, smooth muscle relaxation, and immune modulation. VIP has drawn attention in the mold illness and chronic inflammatory response community, covered in our VIP research guide.

Cholecystokinin (CCK) acts as both a gut hormone (regulating gallbladder contraction and pancreatic secretion) and a brain neuropeptide (modulating anxiety, satiety, and dopamine release). The CCK system illustrates a common theme — many neuropeptides have parallel roles in the brain and the gut.

DSIP (delta-sleep-inducing peptide) is a nine-amino-acid peptide originally isolated from rabbit brain during slow-wave sleep. Its role in sleep regulation remains debated, but research continues into its potential effects on stress and sleep architecture.

Neuropeptides in Brain Function {#neuropeptides-in-brain-function}

Rather than having single, neat functions, neuropeptides typically influence broad functional domains. Here is a summary of which families are most relevant to which brain functions.

Function	Key Neuropeptides
Pain modulation	Endorphins, enkephalins, dynorphins, substance P, CGRP, nociceptin
Appetite and metabolism	NPY, orexins, CCK, PYY, GLP-1, ghrelin, MSH, AgRP
Stress response	CRH, vasopressin, dynorphin, NPY, galanin
Sleep/wake regulation	Orexins, DSIP, galanin, melanin-concentrating hormone
Mood and emotion	Endorphins, oxytocin, CRH, substance P, NPY
Learning and memory	Vasopressin, oxytocin, CCK, substance P, semax
Social behavior	Oxytocin, vasopressin
Reward and addiction	Endorphins, enkephalins, dynorphins, orexins
Immune modulation	VIP, substance P, CGRP, LL-37

A 2025 study in Psychopharmacology highlighted an additional layer of complexity: neuropeptides also regulate astrocytes — the most abundant glial cells in the brain. Central neuropeptides influence astrocyte proliferation, morphology, and secretory functions, which in turn affect the progression of neurodegenerative and neuropsychiatric disorders (Psychopharmacology, 2025). This means neuropeptides shape brain function not just through direct neuronal signaling but also through glial-mediated pathways.

Therapeutic Applications and Drug Development {#therapeutic-applications-and-drug-development}

The neuropeptide field has produced several classes of approved drugs and has many more in clinical pipelines (Kastin et al., 2022).

Approved Drug Classes Based on Neuropeptide Targets

GnRH analogs: Leuprolide, goserelin, nafarelin — for prostate cancer, endometriosis, precocious puberty
Somatostatin analogs: Octreotide, lanreotide — for acromegaly, neuroendocrine tumors
Orexin receptor antagonists: Suvorexant, lemborexant — for insomnia
CGRP pathway drugs: Erenumab, fremanezumab, galcanezumab (antibodies), rimegepant, ubrogepant (small molecules) — for migraine
NK1 receptor antagonists: Aprepitant, rolapitant — for chemotherapy-induced nausea
Vasopressin analogs: Desmopressin — for diabetes insipidus, enuresis
Oxytocin: For labor induction and postpartum hemorrhage
GLP-1 analogs: Semaglutide, liraglutide, tirzepatide — for diabetes and obesity

Active Research Areas

Neurodegeneration. Neuropeptides including GLP-1, PACAP, and orexins are being investigated for neuroprotective effects in Alzheimer's and Parkinson's disease. The success of GLP-1 agonists in metabolic disease has sparked interest in their potential CNS benefits — semaglutide is in Phase III trials for Alzheimer's.

Psychiatric disorders. CRH receptor antagonists for depression, oxytocin for social deficits in autism, NPY analogs for PTSD, and selank for anxiety are all under study. The challenge is that psychiatric neuropeptide signaling involves multiple overlapping systems, making it hard to achieve specific effects without unintended consequences.

Pain management. With the opioid crisis driving demand for non-addictive analgesics, researchers are exploring nociceptin receptor agonists, kappa-opioid agonists with peripherally restricted activity, and CGRP-targeted therapies for pain conditions beyond migraine.

Research Challenges and Future Directions {#research-challenges-and-future-directions}

Despite their therapeutic promise, neuropeptides present formidable development challenges.

The blood-brain barrier. Most neuropeptides cannot cross the BBB after systemic administration. This limits delivery options to intranasal administration, intrathecal injection, or development of small-molecule mimetics that can cross the barrier. It is one reason why CGRP antibodies for migraine — which work peripherally — succeeded commercially while centrally acting neuropeptide drugs have struggled.

Receptor complexity. Neuropeptide signaling involves "ligand and receptor promiscuity" — one peptide may act on multiple receptor subtypes, and one receptor may respond to multiple peptides. Achieving selective pharmacological effects in this tangled network is difficult. Developing highly selective agonists and antagonists for individual receptor subtypes remains an active area of medicinal chemistry.

Short half-lives. Endogenous neuropeptides are rapidly degraded by peptidases, giving them plasma half-lives measured in minutes. Therapeutic development requires either structural modifications for metabolic stability, alternative delivery routes, or small-molecule drugs that mimic or block neuropeptide receptor activity. For a deeper discussion, see our pharmacokinetics guide.

Computational advances. Machine learning and AI-driven approaches are accelerating neuropeptide discovery and optimization. A 2025 review in Computational Biomedicine documented the growing toolbox of computational methods for neuropeptide prediction, including models that identify potential neuropeptide sequences within proteomes and optimize them for research and therapeutic applications (CBM, 2025).

FAQ {#faq}

How many neuropeptides have been identified?

Over 100 neuropeptides have been identified in the mammalian nervous system. The NeuroPep 2.0 database catalogs 5,949 non-redundant neuropeptide entries from 493 organisms across 65 neuropeptide families. This number continues to grow as computational tools and mass spectrometry imaging techniques improve detection of novel neuropeptides.

What is the difference between a neuropeptide and a neurotransmitter?

Classical neurotransmitters (serotonin, dopamine, glutamate, GABA) are small molecules synthesized at the synapse and released for fast, point-to-point signaling. Neuropeptides are larger, synthesized in the cell body, stored in dense-core vesicles, released during intense neuronal firing, and act more slowly over larger distances. Many neurons release both a classical neurotransmitter and one or more neuropeptides — the small molecule handles fast signaling while the peptide modulates circuit behavior over longer timescales.

Can neuropeptides cross the blood-brain barrier?

Most neuropeptides cannot cross the BBB effectively after systemic administration. This is a major barrier to therapeutic development. Strategies to address this include intranasal delivery (which can partially bypass the BBB via olfactory and trigeminal nerve pathways), chemical modifications to improve BBB penetration, development of small-molecule mimetics, and targeted delivery systems like nanoparticles and receptor-mediated transcytosis.

Why are neuropeptide drugs hard to develop?

Three main reasons: (1) the blood-brain barrier blocks most peptides from reaching the brain after systemic dosing; (2) neuropeptide receptor systems are complex, with overlapping ligand-receptor relationships that make selective targeting difficult; and (3) endogenous neuropeptides have very short half-lives, requiring structural modifications or alternative delivery strategies for clinical use.

What are the most successful neuropeptide-based drugs?

The CGRP-targeting migraine drugs (erenumab, fremanezumab) and GLP-1 agonists (semaglutide, tirzepatide) are arguably the most commercially successful. GnRH analogs (leuprolide) have been used for decades in oncology and reproductive medicine. Orexin receptor antagonists (suvorexant) represent a newer class approved for insomnia.

Are nootropic peptides a type of neuropeptide?

Some are. Semax is a synthetic analog of ACTH(4-10), a fragment of the neuropeptide ACTH. Selank is a synthetic analog of the endogenous immunomodulatory peptide tuftsin. Both were developed in Russia and have been studied for cognitive and anxiolytic effects. Other nootropic peptides, like dihexa, are synthetic compounds inspired by neuropeptide biology but not themselves endogenous neuropeptides.

The Bottom Line {#the-bottom-line}

Neuropeptides are the brain's slow, nuanced communication system — the background music that sets the emotional and physiological tone while classical neurotransmitters handle the rapid-fire messaging. From the opioid peptides that regulate pain and reward, to the orexins that keep us awake, to the tachykinins that mediate inflammation and nausea, these molecules influence virtually every aspect of brain function.

The therapeutic track record is mixed but increasingly promising. While many neuropeptide drug candidates have failed in clinical trials (particularly in psychiatry), several classes have been genuinely transformative — CGRP drugs for migraine, GLP-1 agonists for metabolic disease, and GnRH analogs for reproductive conditions. The common thread in successful programs has been a clear understanding of which receptor to target, in which tissue, for which clinical outcome.

For a deeper look at specific neuropeptides discussed here, explore our guides on substance P, oxytocin, DSIP, selank, and semax. For the antimicrobial side of peptide biology — where some neuropeptides pull double duty — see our defensins overview and LL-37 profile.

References {#references}

Wang, Y., et al. (2023). NeuroPep 2.0: An updated database dedicated to neuropeptide and its receptor annotations. Journal of Molecular Biology, 435(22), 168310. ScienceDirect
Hökfelt, T., et al. (2001). Substance P: A pioneer amongst neuropeptides. Journal of Internal Medicine, 249(1), 27-40. Wiley
Bagley, E.E. & Bhatt, D.K. (2019). Opioid peptides. PMC. PMC
Severini, C., et al. (2002). The tachykinin peptide family. Pharmacological Reviews, 54(2), 285-322. PMC
de Lecea, L. (2005). The hypocretin/orexin system. Acta Physiologica, 198(3), 203-208. PMC
Purves, D., et al. (2001). Peptide neurotransmitters. In Neuroscience (2nd edition). NCBI Bookshelf
Chandra, S., et al. (2022). Potentials of neuropeptides as therapeutic agents for neurological diseases. Biomedicines, 10(2), 343. PMC
Vasic, V., et al. (2025). Central neuropeptides as key modulators of astrocyte function in neurodegenerative and neuropsychiatric disorders. Psychopharmacology. Springer
Kumar, S., et al. (2025). A comprehensive review on neuropeptides: Databases and computational tools. Computational Biomedicine. SciExplor
Henry, M.S., et al. (2017). Enkephalins: Endogenous analgesics with an emerging role in stress resilience. Neural Plasticity. PubMed

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