Substance P
SP, TAC1 gene product, tachykinin-1, RPKPQQFFGLM-amide
Substance P is an eleven-amino-acid tachykinin released from sensory nerve endings and from many non-neuronal cells. It is the preferred endogenous ligand at the neurokinin-1 (NK1) receptor and is central to pain transmission, neurogenic inflammation and vomiting. The peptide itself is not a medicine, but drugs blocking its receptor are licensed worldwide.
Mechanism
Substance P is encoded by TAC1 and generated by prohormone convertase processing followed by C-terminal amidation. It acts preferentially at the NK1 receptor (TACR1), a class A GPCR coupling mainly through Gq/11 to phospholipase C, inositol trisphosphate, calcium mobilisation and protein kinase C, with strong beta-arrestin recruitment and rapid internalisation. Affinity for NK2 and NK3 receptors is far lower.
It is stored in large dense-core vesicles in small-diameter C-fibre and A-delta nociceptors and released into laminae I and II of the dorsal horn during sustained noxious input, contributing to wind-up and central sensitisation rather than to first pain. Antidromic peripheral release drives the axon-reflex flare through arteriolar vasodilatation, plasma extravasation and mast cell degranulation. In the area postrema and nucleus tractus solitarius, NK1 signalling mediates the delayed phase of emesis, which is the basis of the licensed antagonists.
What the research shows
The NK1 antagonist programme in chemotherapy-induced nausea and vomiting is one of the cleaner translational successes in neuropeptide pharmacology. Adding aprepitant to a 5-HT3 antagonist plus dexamethasone raised complete response over five days from roughly 52 per cent to 73 per cent in patients receiving high-dose cisplatin, replicated across multinational trials, and fosaprepitant, netupitant and rolapitant followed.
Outside emesis the record is poor. An early Science report suggested the NK1 antagonist aprepitant had antidepressant activity, but a programme of five large randomised trials found no separation from placebo, and development for depression was abandoned. NK1 antagonists have also failed convincingly in analgesia, anxiety, alcohol dependence and in phase 3 trials of serlopitant for chronic pruritus. Substance P blockade does not appear to be a general-purpose central mechanism.
Evidence assessment
High-quality evidence
The strong rating attaches to pharmacological blockade of the NK1 pathway, not to administering the peptide. NK1 antagonists carry regulator-approved labelling in both the US and UK supported by replicated phase 3 trials with verified publications. Substance P itself has never had an approved therapeutic use and there is no evidence base for giving it.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Isolation of a sialogogic peptide from bovine hypothalamic tissue and its characterization as substance P Preclinical only
Established the amino acid sequence of substance P, decades after its original description as an unidentified tissue extract.
Distinct mechanism for antidepressant activity by blockade of central substance P receptors Preclinical only
Reported that the NK1 antagonist aprepitant reduced depression scores comparably to paroxetine. This result did not replicate and should be read as a historical claim, not a current one.
The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin Preclinical only
Aprepitant added to ondansetron and dexamethasone raised five-day complete response from approximately 52 to 73 per cent. A pivotal registration trial.
Lack of efficacy of the substance P (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder Preclinical only
Null result across the trial programme. Directly overturned the 1998 Science finding and ended NK1 antagonist development for depression.
Safety
Substance P is not administered therapeutically. Experimental infusion causes flushing, hypotension, headache and bronchoconstriction through mast cell activation. The licensed antagonists are generally well tolerated but aprepitant is a moderate CYP3A4 inhibitor and inducer of CYP2C9, creating meaningful interactions with dexamethasone, warfarin and hormonal contraception.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No marketing authorisation for substance P; it is an unlicensed substance and supply for human consumption would fall foul of the Human Medicines Regulations 2012. MHRA-authorised NK1 antagonists (including aprepitant, fosaprepitant and netupitant with palonosetron) are available on prescription. |
| United States | Substance P has no FDA approval and is sold only as a research chemical, not for human use. NK1 receptor antagonists (aprepitant, fosaprepitant, netupitant, rolapitant) are FDA-approved for chemotherapy-induced nausea and vomiting. |
| WADA (sport) | Not individually named on the WADA Prohibited List. As a peptide with no regulatory approval for human therapeutic use, it is captured by section S0 (non-approved substances), prohibited at all times. |
Questions
Not on its own in the way people imagine. It amplifies and prolongs pain signalling in the spinal cord during sustained injury, and it drives the redness and swelling of neurogenic inflammation, but blocking it does not produce useful analgesia in humans.
No. It is a peptide destroyed in the gut, cleared from blood within minutes, and has no approved human use. Products marketed on substance P claims are not medicines.