Substance P
tachykinin, precursor 1 | |||||||
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Chr. 7 q21-q22 | |||||||
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Identifiers | |
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ChEBI | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard
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100.046.845 |
IUPHAR/BPS |
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MeSH | Substance+P |
PubChem CID
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UNII | |
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Properties | |
C63H98N18O13S | |
Molar mass | 1347.63 g/mol |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Substance P (SP) is an
with an amide group at the C-terminus.[5] Substance P is released from the terminals of specific
Discovery
The original discovery of Substance P (SP) was in 1931 by
In 1983,
Receptor
The
Substance P and the NK1-receptor are widely distributed in the brain and are found in brain regions that are specific to regulating emotion (
Function
Overview
Substance P ("P" standing for "Preparation" or "Powder") is a neuropeptide – but only nominally so, as it is ubiquitous. Its receptor – the neurokinin type 1 – is distributed over cytoplasmic membranes of many cell types (neurons, glia, endothelia of capillaries and lymphatics, fibroblasts, stem cells, white blood cells) in many tissues and organs. SP amplifies or excites most cellular processes.[16][17]
Substance P is a key first responder to most noxious/extreme stimuli (stressors), i.e., those with a potential to compromise an organism's biological integrity. SP is thus regarded as an immediate defense, stress, repair, survival system. The molecule, which is rapidly inactivated (or at times further activated by peptidases) is rapidly released – repetitively and chronically, as warranted, in the presence of a stressor. Unique among biological processes, SP release (and expression of its NK1 Receptor (through autocrine, paracrine, and endocrine-like processes)) may not naturally subside in diseases marked by chronic inflammation (including cancer). The SP or its NK1R, as well as similar neuropeptides, appear to be vital targets capable of satisfying many unmet medical needs. 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.
Vasodilation
Substance P is a potent
Inflammation
SP initiates expression of almost all known immunological chemical messengers (cytokines).[20][21][22] Also, most of the cytokines, in turn, induce SP and the NK1 receptor.[23][24] SP is particularly excitatory to cell growth and multiplication,[25] via usual,[26] as well as oncogenic drivers.
Pain
Preclinical data support the notion that 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
Mood, anxiety, learning
Substance P has been associated with the regulation of
Vomiting
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. 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.[39]
Cell growth, proliferation, angiogenesis, and migration
The above processes are part and parcel to tissue integrity and repair. Substance P has been known to stimulate cell growth in normal and cancer cell line cultures,[40] and it was shown that substance P could promote wound healing of non-healing ulcers in humans.[41] SP and its induced cytokines promote multiplication of cells required for repair or replacement, growth of new blood vessels,[42] and "leg-like pods" on cells (including cancer cells) bestowing upon them mobility,[43] and metastasis.[44] It has been suggested that cancer exploits the SP-NK1R to progress and metastasize, and that NK1RAs may be useful in the treatment of several cancer types.[45][46][47][48]
Clinical significance
Quantification in disease
Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis;[49] inflammatory bowel disease;[50][51] major depression and related disorders;[52][53][54] fibromyalgia;[55] rheumatological;[56] and infections such as HIV/AIDS and respiratory syncytial virus,[57] as well as in cancer.[58][59] When assayed in the human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable.[60] SP concentrations cannot yet be used to diagnose disease clinically or gauge disease severity. It is not yet known whether changes in concentration of SP or density of its receptors is the cause of any given disease, or an effect.
Blockade for diseases with a chronic immunological component
As increasingly documented, the SP-NK1R system induces or modulates many aspects of the immune response, including WBC production and activation, and cytokine expression,[61] Reciprocally, cytokines may induce expression of SP and its NK1R.[62][63] In this sense, for diseases in which a pro-inflammatory component has been identified or strongly suspected, and for which current treatments are absent or in need of improvement, abrogation of the SP-NK1 system continues to receive focus as a treatment strategy. Currently, the only completely developed method available in that regard is antagonism (blockade, inhibition) of the SP preferring receptor, i.e., by drugs known as neurokinin type 1 antagonists (also termed: SP antagonists, or tachykinin antagonists.) One such drug is aprepitant to prevent the nausea and vomiting that accompanies chemotherapy, typically for cancer. 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.[17][64][65][66]
Dermatological disorders: eczema/psoriasis, chronic pruritus
High levels of
Infections: HIV-AIDS, measles, RSV, others
The role of SP in HIV-AIDS has been well-documented.[61] Doses of aprepitant greater than those tested to date are required for demonstration of full efficacy. 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.[69][70]
Inflammatory bowel disease (IBD)/cystitis
Despite strong preclinical rationale,[75] efforts to demonstrate efficacy of SP antagonists in inflammatory disease have been unproductive. A study in women with IBS confirmed that an NK1RAs antagonist was anxiolytic.[76]
Chemotherapy induced nausea and vomiting
In line with its role as a first line defense system, SP is released when toxicants or poisons come into contact with a range of receptors on cellular elements in the
Other findings
Denervation supersensitivity
When the innervation to substance P nerve terminals is lost, post-synaptic cells compensate for the loss of adequate neurotransmitter by increasing the expression of post-synaptic receptors. 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.
Aggression
Tachykinin / Substance P plays an evolutionarily conserved role in inducing aggressive behaviors.[79] In rodents and cats, activation of hypothalamic neurons which release Substance P induces aggressive behaviors (defensive biting and predatory attack).[80][81][82] Similarly, in fruit flies, tachykinin-releasing neurons have been implicated in aggressive behaviors (lunging).[83][84] In this context, male-specific tachykinin neurons control lunging behaviors that can be modulated by the amount of tachykinin release.[85]
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External links
- Russell J (2001-09-14). "Neurochemical Substance P is Key to Understanding Pain Process". Fibromyalgia Library. ProHealth.com. Retrieved 2008-11-01.
- Fight Club for Flies video, Science Take, New York Times, February 3, 2014