History of Substance P
| Category | Research |
|---|---|
| Also known as | substance P history, von Euler Gaddum, tachykinin |
| Last updated | 2026-04-14 |
| Reading time | 3 min read |
| Tags | historysubstance-ptachykininspainneurokinin |
Overview
Substance P (SP) is an 11-amino-acid peptide belonging to the tachykinin family. It was described in 1931 by Ulf von Euler and John Gaddum at University College London, while they were studying acetylcholine-like activities in intestinal and brain tissue extracts. They discovered a potent smooth muscle-contracting, hypotensive principle distinct from acetylcholine and, lacking a better name, labeled their purified powder "P" — a name that stuck for decades until its structure was finally determined.
The full amino acid sequence of substance P was reported in 1971 by Michael Chang and Susan Leeman at the Brandeis University (later Tufts) laboratories. Their work established SP as the founding member of the tachykinin family, which also includes neurokinin A and neurokinin B in mammals and numerous amphibian analogs such as physalaemin and eledoisin.
Substance P is produced by the tachykinin TAC1 gene, which also encodes neurokinin A. It acts through three G protein-coupled receptors — NK1, NK2, and NK3 — with SP having highest affinity for NK1. SP is richly expressed in primary sensory neurons of the dorsal root ganglia, where it contributes to nociception, inflammation, and neurogenic inflammation.
Key People
- Ulf von Euler (1905–1983): Swedish physiologist and 1970 Nobel laureate who first described substance P.
- John Gaddum (1900–1965): British pharmacologist who co-discovered substance P.
- Susan E. Leeman: American biochemist who led the sequencing of substance P in 1971.
- Michael M. Chang: Leeman's graduate student who performed the sequencing work.
- Vittorio Erspamer (1909–1999): Italian pharmacologist who identified many tachykinin analogs in amphibian skin.
Timeline
- 1931: Von Euler and Gaddum describe "substance P."
- 1953: Erspamer identifies eledoisin from octopus salivary glands.
- 1971: Chang and Leeman publish the amino acid sequence of substance P.
- 1980s: Tachykinin family (neurokinin A, neurokinin B, etc.) is characterized.
- 1987–1989: NK1, NK2, and NK3 receptors are cloned.
- 2003: Aprepitant, an NK1 antagonist, is approved for chemotherapy-induced nausea.
- 2020s: NK1 and NK3 antagonists enter use for itch and menopausal vasomotor symptoms.
Background
Substance P research was essential to establishing that neurons can use peptides — in addition to classical small-molecule transmitters — as signaling molecules. In the 1970s and 1980s, immunohistochemistry mapped SP expression in the central and peripheral nervous systems and demonstrated co-localization with other transmitters. This dramatically expanded the concept of chemical neurotransmission.
SP plays central roles in pain transmission, neurogenic inflammation, smooth muscle contraction (gastrointestinal and airway), and emesis. Through its release from primary afferent neurons into the spinal dorsal horn and into peripheral tissues, it contributes to "triple response" reactions in skin, airway hyperreactivity, migraine pathophysiology, and chemotherapy-induced vomiting.
Modern Relevance
NK1 receptor antagonists (aprepitant, fosaprepitant, rolapitant, netupitant) are routine in preventing chemotherapy-induced nausea and vomiting. NK1 antagonists have also been studied, with more mixed success, in depression, anxiety, pruritus, and skin disease; serlopitant and tradipitant are examples of clinical programs targeting chronic itch and gastroparesis.
NK3 antagonists such as fezolinetant and elinzanetant have been approved or advanced for menopausal hot flashes, exploiting the role of tachykinin signaling in the hypothalamic KNDy (kisspeptin-neurokinin B-dynorphin) neurons that regulate thermoregulation and reproductive hormone release. Substance P research continues to provide new pharmacological avenues, nearly a century after the 1931 discovery. See also bradykinin-discovery.
Related Compounds
Related entries
- The Discovery of Bombesin— Bombesin was isolated in 1971 from European fire-bellied toad skin by Erspamer and colleagues, leading to discovery of its mammalian homolog GRP.
- The Discovery of Bradykinin— Bradykinin, a central mediator of inflammation and vasodilation, was discovered in 1949 by Rocha e Silva, Beraldo, and Rosenfeld in Brazil.
- History of Neuropeptide Y— Neuropeptide Y, one of the most abundant neuropeptides in the brain, was isolated by Tatemoto in 1982 at the Karolinska Institute.