Substance P (SP) was originally discovered in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro. Its tissue distribution and biologic actions were further investigated over the following decades. The eleven-amino-acid structure of the peptide was determined by Susan Leeman in 1971.
In 1983, NKA (previously known as substance K or neuromedin L) was isolated from porcine spinal cord and was also found to stimulate intestinal contraction.
Now in the field of neuroscience, substance P (SP) is a neuropeptide – a substance that functions as a neurotransmitter and as a neuromodulator. To be specific, substance P is an undecapeptide – a peptide composed of a chain of 11 amino acid residues. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:
Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met (RPKPQQFFGLM) with an amidation at the C-terminus. Substance P is released from the terminals of specific sensory nerves, it is found in the brain and spinal cord, and is associated with inflammatory processes and pain.
Substance P is an important element in pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation. Substance P has been associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity, nausea/emesis, pain and nociception. Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury. The regulatory function of SP also involves the regulation of its high-affinity receptor, NK-1. Substance P receptor antagonists may have important therapeutic applications in the treatment of a variety of stress-related illnesses, in addition to their potential as analgesics.
The vomiting center in the medulla contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and opioids. Their activation stimulates the vomiting reflex. Different emetic pathways exist, and substance P/NK1R appears to be within the final common pathway to regulate vomiting. Substance P antagonist (SPA) aprepitant is available in the market in the treatment of chemotherapy-induced nausea/emesis.
Substance P is involved in nociception, transmitting information about tissue damage from peripheral receptors to the central nervous system to be converted to the sensation of pain. It has been theorized that it plays a part in fibromyalgia. Capsaicin has been shown to reduce the levels of substance P, it is presumed, by reducing the number of C-fibre nerves or causing these nerves to be more tolerant. Thus, capsaicin is clinically used as an analgesic and an anti-inflammatory agent to reduce pain associated with arthritis and many types of neuralgia. A role of substance P and NKA in nociception is suggested by the reduction in response thresholds to noxious stimuli by central administration of K2 and K3 agonists. Based on recent studies, it was proposed that NK1, and possibly NK2 receptor antagonists, could be developed as analgesic drugs. It has been studied that the mice carrying a disruption of the gene encoding SP/NKA show severely reduced nociceptive pain responses when the stimuli are moderate to intense. Pain behaviors induced by mechanical, thermal, and chemical stimulation of somatic and visceral tissues were reduced in the mutant mice lacking SP/NKA. However, it has been proposed that the importance of SP and NKA in animal’s pain response apply only to a certain ‘window’ of pain intensities, and, when the intensity of the pain stimuli is further increased, the responses of the knockout mice is not severely different from the wild-type mice.
Substance P increases glutamate activity (NMDA) in central nervous system, and it is associated with the development of brain edema and functional deficits after traumatic brain injury.
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 Harrison S, Geppetti P (June 2001). “Substance P”. The International Journal of Biochemistry & Cell Biology 33 (6): 555–76.  Datar P, Srivastava S, Coutinho E, Govil G (2004). “Substance P: structure, function, and therapeutics”. Current Topics in Medicinal Chemistry 4 (1): 75–103.  Donkin JJ, Nimmo AJ, Cernak I, Blumbergs PC, Vink R (August 2009). “Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury”. J Cereb Blood Flow Metab. 29 (8): 1388–98.