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ENTRIES A–Z
Published in Philip Winn, Dictionary of Biological Psychology, 2003
One of the NEUROPEPTIDES and one of the transmitters most widely distributed in the CENTRAL NERVOUS SYSTEM and the PERIPHERAL NERVOUS SYSTEM. It was discov-ered in 1931 by Von Euler (who was co-winner of the Nobel Prize for Physiology or Medicine in 1970). It is unclear why it is called substance P: the apocryphal story is that it was first synthesized in (P for) powder form. There are three RECEPTOR types, NK1, NK2 and NK3, all G PROTEIN coupled, that bind substance P and NEUROKININ A and NEUROKININ B. (The NK1 receptor is most strongly activated by substance P; NK2 is better activated by the neurokinins, and NK3 is best activated by neurokinin B.) Substance P is co-localized with other neurotransmitters (for example, with ACETYLCHOLINE in some neurons of the PEDUNCULOPONTINE TEGMENTAL NUCLEUS) and has been associated with many different functions, depending on the anatomical localization. It is found in many sites, including the STRIATUM, FRONTAL CORTEX, HYPOTHALAMUS, MIDBRAIN and in many nuclei in the brainstem. It is perhaps best known for its actions in the SPINAL CORD, where it is closely involved in the processing of PAIN. Blockade of substance P action on the C FIBRES of the spinal cord blocks pain perception; GENE KNOCKOUT mice lacking the NK1 receptor in the spinal cord similarly have reduced sensations of pain.
Animal Models of Subtypes of Depression
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
Paul Willner, Paul J. Mitchell
The NK1 receptor is expressed in brain areas associated with the control and management of depressive illness, anxiety, stress, and sensitivity to the rewarding properties of food and drugs of abuse. Indeed, antagonists at the NK1 receptor have been suggested as potential antidepressant drugs with a novel mode of action [89,240,241]. The NK1-receptor knockout mouse is not an animal model of depression. Rather, these mice show behavioral changes similar to those elicited by antidepressants in normal mice, including a decrease in neonatal vocalization following maternal separation, decreased aggressive behavior in the resident-intruder test, and decreased immobility in the forced-swim and tail-suspension tests [241]. NK1-receptor knock-out mice also exhibit a loss of the rewarding properties of morphine, together with reduced physical response to opiate withdrawal, but their response to cocaine is unchanged [197], suggesting that this may reflect a specific interaction with opioid systems, rather than a general effect on brain reward mechanisms.
A pharmacological overview of aprepitant for the prevention of postoperative nausea and vomiting
Published in Expert Review of Clinical Pharmacology, 2023
Andrew Padilla, Ashraf S Habib
Following the observation that substance P induces vomiting [13], studies in animal models in the early 1990s reported that NK1 receptor antagonists (NK1RAs) cross the blood-brain barrier and were effective in preventing vomiting [14]. In 1997, CP-122,721 was the first NK1RA investigated in humans and proved to be effective in preventing delayed vomiting in patients receiving cisplatin [15]. This was also subsequently shown to be effective for PONV prophylaxis in women undergoing hysterectomy [16]. NK1RAs bind to the nucleus tractus solitarius lying ventrally to the area postrema in the so-called subnucleus gelatinosus. A peripheral mechanism of action also involves antagonism of the NK1 receptors located on the vagal terminals in the gut.
Evolution of the drug-target residence time model
Published in Expert Opinion on Drug Discovery, 2021
Similarly, Nederpelt et al. [31] demonstrated that the insurmountability of NK1 receptor antagonists was dependent on their drug-target residence time, but was also influenced by the agonist-target residence time of the competing endogenous agonists of this receptor. For example, antagonistic efficacy was greatest for the slowly dissociating antagonist aprepitant when competing with the slowly associating agonist NKA and least efficacious for the combination of the rapidly dissociating antagonist DFA with the rapidly associating agonist SP. This important study adds a temporal dimension to the concept of intracellular competition between drugs and endogenous substrates/agonists of their intended target proteins.
Therapy for pruritus in the elderly: a review of treatment developments
Published in Expert Opinion on Pharmacotherapy, 2018
Manuel P. Pereira, Sonja Ständer
Novel agents, especially opioid targeting drugs and neurokinin-1 receptor antagonists, have shown promising results in clinical trials. NK1 receptor antagonists exhibit low rates of side effects, while opioid targeting drugs may have fewer side effects in the early phase of therapy. Although they have not been specifically tested in older demographic groups in an own trial, some indications that have been targeted, such as chronic prurigo, have a high prevalence in older patients and many patients >65 years have been included in studies. Future analyses should aim to clarify the side effect profile in this population.