What is Substance P?
Substance P (SP) is an 11-amino-acid endogenous neuropeptide of the tachykinin family. First isolated in 1931 by von Euler and Gaddum (the "P" stands for "powder," referring to the original purification), it is one of the most-studied neuropeptides in physiology and remains the canonical agonist of the neurokinin-1 (NK1) receptor.
Substance P is not a therapeutic drug — it is an endogenous signaling peptide. It is widely used in research as a probe of NK1-receptor function, neurogenic inflammation, and tachykinin biology. There are several NK1 receptor antagonists that have reached clinical use (aprepitant, fosaprepitant, rolapitant, casopitant, netupitant) — these are small molecules that block substance P signaling and are used primarily for chemotherapy-induced nausea and vomiting.
Structure
Native substance P sequence: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2
It is the prototype tachykinin, a family characterized by a conserved C-terminal sequence (Phe-X-Gly-Leu-Met-NH2) responsible for receptor binding.
Mechanism and Functions
Substance P binds the NK1 receptor (G-protein coupled, primarily Gq-coupled) and to a lesser extent NK2 and NK3 receptors. It is released from:
- Primary afferent C-fibers in skin, mucosa, and viscera (peripheral)
- Specific brainstem and limbic neurons (central)
Functions:
- Neurogenic inflammation — vasodilation, plasma extravasation, mast cell degranulation
- Pain transmission — first central synapse in the dorsal horn, contributing to chronic pain and central sensitization
- Wound healing — promotes angiogenesis, fibroblast proliferation, and epithelial migration in skin and corneal wounds
- Mood and stress — central NK1 signaling modulates anxiety, depression, and stress response
- Itch transmission — substance P from sensory neurons mediates a major component of pruritic signaling
- Vomiting reflex — central NK1 signaling in the area postrema drives emesis (the rationale for NK1 antagonist antiemetics)
Research Use
Substance P is used as a research peptide for:
- NK1 receptor characterization and activation studies
- Models of neurogenic inflammation (nasal, airway, dermal)
- Wound healing studies (corneal, diabetic foot ulcer models)
- Pain research (spinal cord, dorsal root ganglion)
- Mast cell biology
- Animal behavioral models of anxiety and depression
Therapeutic Status
Substance P itself has no approved therapeutic use. The clinically relevant drugs in the substance P pathway are NK1 antagonists (small molecules):
- Aprepitant (Emend) — FDA 2003, chemotherapy-induced nausea and vomiting
- Fosaprepitant (Emend IV) — FDA 2008, IV form
- Netupitant + palonosetron (Akynzeo) — FDA 2014
- Rolapitant (Varubi) — FDA 2015
These antagonists work by blocking substance P's effect at the NK1 receptor, reducing nausea and vomiting after chemotherapy.
Distinction from Other Neuropeptides
Substance P is one of several neuropeptides relevant to chronic pain, inflammation, and wound healing:
- Substance P — primary tachykinin in pain, inflammation, mast cell activation
- CGRP (calcitonin gene-related peptide) — vasodilation, migraine pathophysiology
- VIP (vasoactive intestinal peptide) — vasodilation, immune modulation
- Neurokinin A and B — other tachykinins with overlapping but distinct receptor preferences
Place in Research
Substance P remains in active research as a probe of neurogenic inflammation and wound-healing biology. It is sold by research chemical suppliers as a high-purity peptide for laboratory use.