Peptide Basics
Substance P: The Eleven-Amino-Acid Pain and Inflammation Peptide, Its NK1 Receptor and the Medicines That Block It
Substance P is a neuropeptide of eleven amino acids, one of the tachykinins, that carries pain signals, contracts gut muscle and drives inflammation; its main receptor is the neurokinin-1 (NK1) receptor. This page sets out where it comes from, its sister peptides neurokinin A and B, its three receptors, how it is broken down, and the medicines in FDA’s records that block its receptor. Every figure is taken from UniProt, PubChem, MeSH, PubMed or FDA’s own databases and labels.
What substance P is
MeSH, the U.S. National Library of Medicine’s subject index, describes substance P as an eleven-amino-acid neurotransmitter found in both the central and the peripheral nervous system. It is involved in the transmission of pain, causes rapid contractions of the smooth muscle of the gut, and modulates inflammatory and immune responses. That is why MeSH files it among the neuropeptides.
Its sequence reads RPKPQQFFGLM: arginine, proline, lysine, proline, glutamine, glutamine, phenylalanine, phenylalanine, glycine, leucine, methionine, and UniProt records that the final methionine carries an amide group in place of the usual acid end. PubChem gives a molecular formula of C63H98N18O13S and a molecular weight of 1,347.6 (CID 36511).
It is the best-known member of the tachykinins. MeSH defines the family by a shared ending, Phe-X-Gly-Leu-Met-NH2, in which X is an aromatic or a branched amino acid, and records members in mammals, amphibians and molluscs. In people the other two are neurokinin A and neurokinin B. In PubMed’s records, substance P was isolated from bovine hypothalamus as a peptide that stimulates saliva in 1970 (PMID 5456150), and its amino-acid sequence and a synthesis were published together in 1971 (PMID 5285346 and 5285347).
Sources: MeSH D013373 and D015320; UniProt P20366; PubChem CID 36511; PubMed 5456150, 5285346, 5285347. Read 10 November 2026.
Where it comes from: the TAC1 precursor
Substance P is cut from a 129-amino-acid precursor, protachykinin-1, made from the TAC1 gene. The same precursor holds more than one tachykinin. UniProt maps it like this:
| Piece | Positions | Amino acids | Note |
|---|---|---|---|
| Signal peptide | 1-19 | 19 | Steers the precursor out of the cell; removed first. |
| Propeptide | 20-56 | 37 | A spacer cut away during processing. |
| Substance P | 58-68 | 11 | RPKPQQFFGLM, with the final methionine converted to an amide. |
| Neuropeptide K | 72-107 | 36 | A longer peptide that ends in the same ten amino acids as neurokinin A. |
| Neuropeptide gamma | 72-73 + 89-107 | 21 | Neuropeptide K with a stretch missing, joined from two parts. |
| Neurokinin A | 98-107 | 10 | HKTDSFVGLM, also amidated at the end; the second tachykinin from this gene. |
| C-terminal flanking peptide | 111-126 | 16 | The tail of the precursor, after the last tachykinin. |
UniProt records four forms of the TAC1 product (alpha, beta, gamma and delta), made by joining the gene’s pieces in different ways. Neurokinin B comes from a separate gene, TAC3: UniProt places its ten amino acids, DMHDFFVGLM, at positions 81 to 90 of a 121-amino-acid precursor. The first piece of each precursor is a signal sequence, explained on our signal peptides page.
Sources: UniProt P20366 (TAC1) and Q9UHF0 (TAC3); MeSH D015288. Read 10 November 2026.
What substance P does
UniProt describes the tachykinins as peptides that excite neurons, evoke behavioural responses, widen blood vessels, stimulate glands to secrete, and contract many smooth muscles, directly or indirectly. For substance P it adds that it is released from the endings of particular sensory nerves.
From there it acts on mast cells through a receptor called MRGPRX2. UniProt describes the result as neurogenic inflammation, inflammation started by nerves: mast cells are activated, immune cells are recruited and inflammatory messengers such as cytokines are released. That response can in turn activate or sensitise the nerve endings that sense pain. MeSH summarises the same picture as a role in pain transmission and in modulating inflammatory and immune responses, and adds the rapid contraction of gut smooth muscle.
Sources: UniProt P20366; MeSH D013373. Read 10 November 2026.
The three neurokinin receptors, NK1 to NK3
The tachykinins act through three G protein-coupled receptors. Each recognises all three peptides but prefers one, and UniProt gives the order of preference for each:
| Receptor (gene) | Amino acids | Preference | Note |
|---|---|---|---|
| NK1 (TACR1) | 407 | Substance P first, then neurokinin A, then neurokinin B | MeSH: central and peripheral neurons, smooth muscle, gland (acinar) cells, vessel lining, fibroblasts and immune cells |
| NK2 (TACR2) | 398 | Neurokinin A first, then neurokinin B, then substance P | UniProt records it as the receptor for neurokinin A (substance K) |
| NK3 (TACR3) | 465 | Neurokinin B first, then neurokinin A and substance P | UniProt records substance P as a low-affinity agonist here |
UniProt records that substance P binding to NK1 activates phospholipase C and also raises cyclic AMP inside the cell. MRGPRX2, the mast-cell receptor described above, is a fourth receptor for substance P outside the neurokinin family.
Sources: UniProt P25103 (TACR1), P21452 (TACR2), P29371 (TACR3) and P20366; MeSH D018040. Read 10 November 2026.
How substance P is broken down
UniProt records that substance P is cleaved and degraded by two enzymes, angiotensin-converting enzyme (ACE) and neprilysin, and that a third, FAP, cuts it at one position in laboratory tests. ACE is the same enzyme that inactivates bradykinin and converts angiotensin I into angiotensin II.
Source: UniProt P20366 (post-translational modification). Read 10 November 2026.
Medicines that block substance P’s receptors: what FDA’s records show
MeSH files neurokinin-1 receptor antagonists as their own class: compounds that block the NK1 receptor. The aprepitant labels describe it as a selective, high-affinity antagonist of the human substance P/NK1 receptor, with little or no affinity for the serotonin, dopamine and corticosteroid receptors, which the labels name as the targets of existing anti-sickness therapies. The table lists the NK1 and NK3 blockers in Drugs@FDA by the approval year recorded for each original application:
| Medicine | Application | Approved | What it blocks and what the label names it for |
|---|---|---|---|
| Emend (aprepitant) | NDA 021549 | 2003 | Blocks NK1. The first NK1 blocker in Drugs@FDA; current aprepitant capsule labels name prevention of nausea and vomiting with cancer chemotherapy, with other antiemetics, and after surgery in adults. Generic capsules are recorded from 2012. |
| Emend (fosaprepitant) | NDA 022023 | 2008 | A prodrug: its label states the effect is attributable to aprepitant. Labelled, with other antiemetics, to prevent chemotherapy-induced nausea and vomiting from 6 months of age. |
| Akynzeo (netupitant + palonosetron) | NDA 205718 | 2014 | Combines an NK1 blocker with a serotonin 5-HT3 blocker; labelled with dexamethasone for chemotherapy-induced nausea and vomiting in adults. A fosnetupitant version is recorded in 2018 (NDA 210493). |
| Varubi (rolapitant) | NDA 206500 | 2015 | Blocks NK1; its label states no significant affinity for NK2 or NK3. Labelled for delayed chemotherapy-induced nausea and vomiting in adults. |
| Cinvanti (aprepitant) | NDA 209296 | 2017 | Another aprepitant product; labelled for chemotherapy-induced nausea and vomiting in adults. |
| Aponvie (aprepitant) | NDA 216457 | 2022 | Labelled for prevention of postoperative nausea and vomiting in adults; not studied for treating nausea that has already started. |
| Veozah (fezolinetant) | NDA 216578 | 2023 | Blocks NK3, the neurokinin B receptor, not NK1. Labelled for moderate to severe hot flushes and night sweats (vasomotor symptoms) due to menopause. |
| Lynkuet (elinzanetant) | NDA 219469 | 2025 | Blocks both NK1 and NK3, so both substance P and neurokinin B signalling. Labelled for the same menopause indication. |
None of them is a peptide. PubChem gives aprepitant the formula C23H21F7N4O3 and a weight of 534.4, rolapitant C25H26F6N2O2 (500.5) and netupitant C30H32F6N4O (578.6): small molecules built to keep substance P, or neurokinin B, off its receptor. Drugs@FDA also records further aprepitant and fosaprepitant products from other applicants up to 2026; the table shows the original application of each medicine and is not a list of every product.
Sources: Drugs@FDA via openFDA (original approval dates); current U.S. labels for Emend for injection, aprepitant capsules, Akynzeo, Varubi, Cinvanti, Aponvie, Veozah and Lynkuet (indications, mechanism of action); MeSH D064729; PubChem CID 135413536, 10311306 and 6451149. Read 10 November 2026. Doses are not reproduced here; the approved medicines that are themselves peptides are on our FDA-approved peptides page.
Medibact does not manufacture or sell peptides. We supply USP-grade bacteriostatic water, made in the USA, for research use only, and publish reference material like this page.
Where this sits in the rest of the reference
FAQ
What is substance P?
Substance P is a peptide of eleven amino acids, RPKPQQFFGLM, whose last amino acid carries an amide group. MeSH, the U.S. National Library of Medicine's subject index, describes it as a neurotransmitter of both the central and peripheral nervous systems that is involved in the transmission of pain, causes rapid contractions of the smooth muscle of the gut and modulates inflammatory and immune responses. It belongs to the tachykinins, a family of peptides that share the same ending.
What does substance P do?
UniProt describes the tachykinins as peptides that excite neurons, evoke behavioural responses, widen blood vessels, stimulate secretion and contract many smooth muscles. For substance P specifically it records release from the endings of particular sensory nerves, signalling through the NK1 receptor, and activation of mast cells through a receptor called MRGPRX2, which drives neurogenic inflammation and pain.
Is substance P a neurotransmitter or a hormone?
Its main records describe it as a nervous-system messenger. MeSH files it as a neurotransmitter of the central and peripheral nervous systems, and UniProt calls it a secretagogue neuropeptide released from sensory nerve endings. That is why it appears on our neuropeptides page alongside the endorphins, neuropeptide Y and the orexins.
How is substance P made?
It is cut from a 129-amino-acid precursor, protachykinin-1, made from the TAC1 gene. UniProt maps substance P to positions 58 to 68 of that precursor and records that the same precursor also yields neurokinin A, neuropeptide K and neuropeptide gamma. A separate gene, TAC3, makes neurokinin B, the third mammalian tachykinin.
What receptor does substance P bind to?
Mainly the neurokinin-1 (NK1) receptor. UniProt records that NK1 prefers substance P over neurokinin A and neurokinin B, while NK2 prefers neurokinin A and NK3 prefers neurokinin B; substance P can still act on NK3, but with low affinity. UniProt also lists MRGPRX2 on mast cells as a substance P receptor. All of them are G protein-coupled receptors.
What does substance P have to do with pain?
MeSH lists pain transmission among substance P's roles, and UniProt records that, released from sensory nerve endings, it activates mast cells and starts neurogenic inflammation, which can activate or sensitise the nerve endings that sense pain. This page describes those records; it does not offer any treatment or advice for pain.
How is substance P broken down?
UniProt records that substance P is cleaved and degraded by angiotensin-converting enzyme (ACE) and by neprilysin, and that the enzyme FAP can cut it at one position in laboratory tests. ACE is the same enzyme that inactivates bradykinin and makes angiotensin II.
Which medicines block substance P?
Drugs@FDA records several NK1 receptor blockers: aprepitant (Emend, from 2003), its prodrug fosaprepitant (2008), netupitant in combination with palonosetron (Akynzeo, 2014) and rolapitant (Varubi, 2015). Their labels name the prevention of nausea and vomiting with cancer chemotherapy, and for some aprepitant products after surgery. Elinzanetant (Lynkuet, 2025) blocks NK1 and NK3 and is labelled for menopausal hot flushes; fezolinetant (Veozah, 2023) blocks NK3 only.
Is aprepitant a peptide?
No. PubChem gives aprepitant the formula C23H21F7N4O3 and a molecular weight of 534.4, a small molecule, against 1,347.6 for substance P itself. None of the NK receptor blockers in the table on this page is a peptide. Substance P is the peptide; the medicines are built to stop it, or neurokinin B, reaching its receptor.
Is this medical advice?
No. This page explains what substance P is, from public scientific and regulatory sources. It gives no dose, schedule or recommendation; anyone treated with these medicines should follow their own clinician and product label. Peptides sold for research are labelled research use only, not for human use. Medibact supplies USP-grade bacteriostatic water, made in the USA, and is not affiliated with any manufacturer of the products named here.
References: UniProt P20366, Q9UHF0, P25103, P21452, P29371; MeSH D013373, D015320, D015288, D018040, D064729; PubChem CID 36511, 135413536, 135413538, 10311306, 6451149; PubMed 5456150, 5285346, 5285347; Drugs@FDA via openFDA and the current U.S. labels named above. Read 10 November 2026.
Educational use only — not medical advice. This guide summarizes information reported in published research and community practice for educational purposes. It is not medical advice and not a recommendation to use any compound. Any doses, schedules, or combinations shown are examples of what has been reported, not instructions for you. Many peptides described here are research compounds that are not FDA-approved for the uses discussed and may be investigational or restricted. Effects, risks, and legal status vary; individual needs and results vary. Consult a qualified, licensed healthcare professional before making any decision. Do not use this content to diagnose, treat, or dose yourself.