Substance P is an 11-amino-acid neuropeptide (sequence: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, MW ~1347.6 g/mol) belonging to the tachykinin family. It is widely distributed in the central and peripheral nervous systems, where it functions as a neurotransmitter and neuromodulator involved in pain transmission, inflammation, and emesis. Substance P is the primary endogenous agonist of the neurokinin-1 receptor (NK1R) and is the pharmacological target of the antiemetic drug aprepitant (Emend).
Category: Neuropeptide / Reference. Evidence rating: B (meaningful human data).
Clinical status: Endogenous neuropeptide. Not a drug. NK1R antagonists (aprepitant, fosaprepitant, netupitant) are FDA-approved antiemetics. NK1R antagonists for depression showed mixed clinical results.
Substance P preferentially binds the neurokinin-1 receptor (NK1R), a G-protein-coupled receptor (Gq/11-coupled) expressed in the CNS, peripheral sensory neurons, immune cells, and GI tract. Activation of NK1R stimulates phospholipase C, producing IP3 and DAG, leading to intracellular calcium…
Safety considerations: Endogenous neuropeptide — not administered as a drug; Exogenous substance P injection causes pain, flushing, and hypotension; NK1R antagonists (the therapeutic approach) have well-characterized safety profiles.
Reviewed by the PeptideAtlas Editorial Team. Last reviewed: 2026-08-12.
Related peptides: Neuropeptide Y, VIP (Vasoactive Intestinal Peptide), PACAP.
Compare: Substance P vs Neuropeptide Y, Substance P vs VIP (Vasoactive Intestinal Peptide), Substance P vs PACAP.
Substance P is the endogenous agonist of the NK1 receptor. Aprepitant (Emend) is a synthetic NK1R antagonist that blocks substance P signaling. By blocking NK1R in the brainstem vomiting center, aprepitant prevents chemotherapy-induced nausea and vomiting.
Substance P contributes to pain signaling but does not directly cause pain sensation. It is released from sensory nerve terminals in the spinal cord dorsal horn and amplifies nociceptive transmission. It also causes neurogenic inflammation in peripheral tissues, which sensitizes nociceptors.
Despite a promising Phase II trial (Kramer et al., Science 1998), larger Phase III trials of NK1R antagonists for depression produced inconsistent results. The initial positive findings may have reflected an unusually high placebo response or specific patient selection. The antidepressant mechanism of NK1R blockade remains debated.