[2][3] Substance P and the closely related neurokinin A (NKA) are produced from a polyprotein precursor after alternative splicing of the preprotachykinin A gene.

The original discovery of Substance P (SP) was in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro.

[7] In 1983, Neurokinin A (previously known as substance K or neuromedin L) was isolated from porcine spinal cord and was also found to stimulate intestinal contraction.

Amino acid residues that are responsible for the binding of SP and its antagonists are present in the extracellular loops and transmembrane regions of NK-1.

The failure of clinical proof of concept studies, designed to confirm various preclinical predictions of efficacy, is currently a source of frustration and confusion among biomedical researchers.

In contrast to other neuropeptides studied in human skin, substance P-induced vasodilation has been found to decline during continuous infusion.

The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system.

[29] Unfortunately, the reasons why NK1 receptor antagonists have failed as efficacious analgesics in well-conducted clinical proof of concept studies have not yet been persuasively elucidated.

Substance P has been associated with the regulation of mood disorders, anxiety, stress,[31] reinforcement,[32] neurogenesis,[33] synaptic growth and dendritic arborisation,[34] respiratory rhythm,[35] neurotoxicity, pain, and nociception.

[38] The vomiting center in the medulla, called the area postrema, contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and endogenous opioids.

With the exception of chemotherapy-induced nausea and vomiting, the patho-physiological basis of many of the disease groups listed below, for which NK1RAs have been studied as a therapeutic intervention, are to varying extents hypothesized to be initiated or advanced by a chronic non-homeostatic inflammatory response.

Respiratory syncytial and related viruses appear to upregulate SP receptors, and rat studies suggest that NK1RAs may be useful in treating or limiting long term sequelae from such infections.

Presumably, SP is released in or around the nucleus of the solitary tract upon integrated activity of dopamine, serotonin, opioid, and/or acetylcholine receptor signaling.

In turn, a fairly complex reflex is triggered involving cranial nerves responsible for respiration, retroperistalsis, and general autonomic discharge.

[77] However, given that NK1Rs are unprotected by a blood brain barrier in the area postrema just adjacent to neuronal structures in the medulla, and the activity of sendide (the peptide based NK1RA) against cisplatin-induced emesis in the ferret,[78] it is likely that some peripheral exposure contributes to antiemetic effects, even if through vagal terminals in the clinical setting.

These radiolabeled compounds are designed to bind specifically to NK-1 receptors on glioma cells, allowing for both imaging (via 99mTc) and therapeutic (via 177Lu) applications.

The study highlights the promising role of NK-1 receptor-targeted strategies in improving glioma diagnosis and treatment through receptor-specific delivery of radioisotopes.

This, ultimately, leads to a condition known as denervation supersensitivity as the post-synaptic nerves will become hypersensitive to any release of substance P into the synaptic cleft.

[80] In rodents and cats, activation of hypothalamic neurons which release Substance P induces aggressive behaviors (defensive biting and predatory attack).