Substance P


Substance P (SP) is a peptide composed of a chain of 11 amino acid residues.

It is a type of neuropeptide, belonging to the tachykinin family of neuropeptides. 

SP acts as a neurotransmitter and a neuromodulator.

Substance P is a neuropeptide, which means it is a small protein-like molecule used by nerve cells to communicate with one another. 

It serves as a neurotransmitter and is involved in the transmission of pain signals. 

Substance P is present in significant levels and may help facilitate the production of saliva, smooth muscle contractions, and other tissue responses.

Substance P is found in the brain and spinal cord, as well as in the peripheral nervous system. 

It plays a role in regulating mood, anxiety, stress, and pain perception. 

it is also involved in the body’s inflammatory response.

Substance P is released from the terminals of specific sensory nerves. 

SP is found in the brain and spinal cord and is associated with inflammatory processes and pain.

Its endogenous receptor is neurokinin 1 receptor (NK1-receptor, NK1R).

Substance P and the NK1-receptor are widely distributed in the brain.

They are found in brain regions that are specific to regulating emotion: hypothalamus, amygdala, and the periaqueductal gray.

Substance P and the NK1-receptor are found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the antidepressant drugs.

SP can induce the cytokines that are capable of inducing NK-1 transcription factors.[15]

Substance P is a ubiquitous neuropeptide.

 Substance P’s  receptor is the neurokinin type 1, which is distributed over cytoplasmic membranes of cell types including neurons, glia, endothelia of capillaries and lymphatics, fibroblasts, stem cells, white blood cells in many other tissues and organs.

SP amplifies or excites most cellular processes.

It is  a first response to most noxious/extreme stimuli with a potential to compromise biological integrity.

It is an immediate defense, stress, repair, survival system. 

The SP molecule is rapidly inactivated and is is rapidly released in a repetitive and chronic manner, as warranted, in the presence of a stressor. 

Problematic is that 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.

Substance P is a potent vasodilator dependent on nitric oxide release.

It is involved in the axon reflex-mediated vasodilation to local heating and wheal and flare reaction in the skin.

It has been shown that vasodilation to substance P is dependent on the NK1 receptor located on the endothelium. 

SP initiates expression of almost all known immunological chemical messengers-cytokines).

Most of the cytokines, in turn, induce SP and the NK1 receptor.

SP is particularly excitatory to cell growth and multiplication, via usual and oncogenic drivers. 

It triggers nausea and emesis.

Substance P and other sensory neuropeptides when released from the sensory nerve fibers in the skin, muscle, and joints are is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury.

Substance P is an important element in pain perception, relating to the transmission of pain information into the central nervous system. 

It coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation.

Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle, and joints. 

This release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury.

Substance P has been associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, synaptic growth and dendritic arborization, respiratory rhythm neurotoxicity, pain, and nociception.

Substance P may play a critical role in long-term potentiation of aversive stimuli. 

The vomiting center in the medulla, called the area postrema, contains high concentrations of substance P and its receptor.

The area postrema, in addition contains other neurotransmitters such as choline, histamine, dopamine, serotonin, and endogenous opioids. 

The  activation of these neurotransmitters stimulate the vomiting reflex. 

Different emetic pathways exist, and substance P/NK1R appears to be within the final common pathway to regulate vomiting.

Substance P has been known to stimulate cell growth in normal and cancer cell line cultures, and it was shown that substance P could promote wound healing of non-healing ulcers in humans.

SP and the  cytokines it induces promote multiplication of cells required for repair or replacement, growth of new blood vessels, and 

bestows upon them mobility, and metastasis.

Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has is associated with many diseases: sickle cell crisis, inflammatory bowel disease, major depression, fibromyalgia, rheumatological, and infections such as HIV/AIDS and respiratory syncytial virus, as well as in cancer.

The SP-NK1R system induces or modulates many aspects of the immune response, including WBC production and activation, and cytokine expression,

Cytokines may induce expression of SP and its NK1R.

Currently, the only completely developed method available for antagonism (blockade, inhibition) of the SP preferring receptor, is by drugs known as neurokinin type 1 antagonists (also termed: SP antagonists, or tachykinin antagonists.

Aprepitant prevents nausea and vomiting that accompanies chemotherapy.

Dermatological disorders: eczema/psoriasis, chronic pruritus: 

High levels of BDNF and substance P have been found associated with increased itching in eczema.

Infections: HIV-AIDS, Measles, RSV,  and others are associated with unregulated SPs.

Entamoeba histolytica protozoa is  found to secrete serotonin as well as substance P and neurotensin.

SP is released when toxicants or poisons come into contact with a range of receptors on cellular elements in the chemoreceptor trigger zone, located in the floor of the fourth ventricle of the brain, the area postrema.

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

It stimulates NK1Rs causing a fairly complex reflex involving cranial nerves responsible for respiration, retroperistalsis, and general autonomic discharge. 

The actions of aprepitant are said to be entirely central, thus requiring passage of the drug into the central nervous system, given that NK1Rs are unprotected by a blood brain barrier in the area postrema just adjacent to neuronal structures in the medulla.

Denervation supersensitivity occurs when the innervation to substance P nerve terminals is lost, and post-synaptic cells compensate for the loss of adequate neurotransmitter by increasing the expression of post-synaptic receptors: this leads to a condition of the  post-synaptic nerves becoming hypersensitive to any release of substance P into the synaptic cleft.

Substance P plays an evolutionarily conserved role in inducing aggressive behaviors.

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