Substance p

Substance P is a neuropeptide of the tachycin group consisting of 11 amino acids (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2). Neuropeptides of the tachykinin family are encoded by 2 genes: preprotachykinin-A (PPT-A) and preprotachykinin-B (PPT-B). Substance P is translated by the PPT-A gene. Substance P binds to specific receptors (Mantyh PW 2002).

4 types of substance P receptors are known:

• Neurokinin-1 receptor, NK-1
• Neurokinin-2 receptor, NK-2
• neurokinin-3 receptor, NK-3 and
• Neurokinin-4 receptor, NK-4.

The substance P is produced by nerve cells, but also by leukocytes. Leukocytes express both substance P and the neurokinin-1 receptor.

The neuropeptide "substance P" is found in primarily afferent neurons and is considered, together with other peptides (e.g. calcitonin gene related peptides) and glutamate, to be a co-transmitter of these neurons. It is involved in various physiological and pathological processes such as learning and memory, pain processing and affective disorders. Substance P causes pain via nosoreceptive receptors at sensitive nerve endings, vasodilation via smooth muscle fibers and salivation.

NK-1 receptors are centrally located in limbic areas such as the amygdala, septum, hippocampus and hypothalamus, with only 5% to 7% of neurons expressing NK receptors (Mantyh PW 2002).

Peripherally, substance P is mainly located in enteric (Satheeshkumar PS et al. 2014) and primarily sensory neurons. In the gastrointestinal tract NK-1, NK-2 and NK-3 receptors on enteric neurons, in smooth muscle, epithelia, vessels and immune cells serve as target receptors. NK-4 receptors are predominantly found in muscle tissue and bind preferentially neurokinin A.

Substance P as a modulator of inflammatory processes: Substance P is a modulator of inflammatory including allergic (Sun J et al. 2014) processes by stimulating professional phagocytes (analogous to Tuftsin). The neuropeptide also stimulates the "alarm cytokines" of inflammation, such as tumor necrosis factor alpha, interleukin-1, interleukin-6 (acute phase reaction) and prostaglandins. In the axon reflex, substance P activates mast cells and induces histamine release. Furthermore, substance P regulates the chemotaxis of leukocytes.

Immunocompetent cells are physiologically stimulated by peptidergically innervated lymphoid tissue. NK receptors have been identified by detecting mRNA on B and T lymphocytes as well as on monocytes and macrophages (Mashaghi A et al. 2016). Substance P is found in neutrophil and eosinophil granulocytes, in monocytes/macrophages, in Leydig's cells and in endothelia.

Substance P stimulates the proliferation of T cells and leads to increased Ig production in B lymphoma cells. Macrophages and monocytes are stimulated to secrete various cytokines such as interleukin-1, interleukin-6, interleukin-10, interleukin-12 and TNF-alpha.

Substance P promotes mast cell degranulation. Furthermore, the phagocytosis capacity of neutrophil granulocytes and macrophages is increased.

Inflammatory reactions are influenced by stimulation of interleukin-8 production in macrophages and lymphocytes as well as by an increase in superoxide production by SP. Thus, substance P is detectable in chronically inflamed tissue and enhances the inflammatory effects of bradykinin and prostaglandin E1. In addition, an autocrine stimulation of lymphocytes via SP can also be assumed, as lymphocytes and macrophages both express the NK-1 receptor and synthesize SP.

Interactions between substance P and immunocompetent cells are also detectable in the defense system of the central nervous system. Substance P leads to increased production of interleukin-1 and interleukin-6 in astrocytes and microglia. Substance P increases the release of prostaglandin E and thromboxane B2 from astrocytes. It was shown that substance P activates the p38 MAPK (mitogen-activated protein kinases) in a dose- and time-dependent manner.

An excess of substance P is discussed as a possible cause of fibromyalgia.

The substance P/NK1 receptor system can induce the proliferation and migration of tumor cells. It also stimulates tumor-associated angiogenesis. Corresponding antagonists represent potential therapeutic approaches (Mander K et al. 2013)

Capsaicin, a substance made from paprika and chilli, can lower the substance P level.

Another hint: The letter P originally stood for powder, because the substance was present in the form of a powder, today the P is interpreted as pain.

1. de Avila ED et al (2014) Relationship between levels of neuropeptide Substance P in periodontal disease and chronic pain: a literature review. J Investig Clin Dent 5:91-97.
2. Mander K et al (2014) Advancing drug therapy for brain tumours: a current review of the pro-inflammatory peptide Substance P and its antagonists as anti-cancer agents. Recent Pat CNS Drug Discov 9:110-121.
3. Mantyh PW (2002). Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 63 Suppl 11:6-10.
4. Mashaghi A et al (2016) Neuropeptides substance P and the immune response. Cell Mol Life Sci 73:4249-4264.
5. Muñoz M et al (2013) Involvement of substance P and the NK-1 receptor in cancer progression. Peptides 48:1-9.satheeshkumar PS et al.(2014) Tachykinin peptides, substance P, and its receptor NK-1R play an important role in alimentary tract mucosal inflammation during cytotoxic therapy. Dig Dis Sci 59:2864-2873.
6. Sun J et al(2014) Substance P at the neuro-immune crosstalk in the modulation of inflammation, asthma and antimicrobial host defense. Inflammation allergy drug targets 13:112-120.
7. Vine JV (2015) Substance P and the regulation of inflammation in infections and inflammatory bowel disease. Acta Physiol (Oxf) 213:453-461.