Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent immunohistochemical studies have shown the distribution of histaminergic neurons in the mammalian brain, which are concentrated in the tuberomammillary nucleus of the posterior hypothalamus and project efferent fibers to almost all parts of the brain from the olfactory bulb to the spinal cord. Histaminergic neurons co-express other neuroactive substances, such as gamma-aminobutyric acid, adenosine, substance P, galanin and Met-enkephalin-Arg-Phe. In addition, pharmacological studies have demonstrated the presence of presynaptic histamine H3-receptors (autoreceptor) in addition to H1- and H2-receptors. The specific agonist (alpha-methylhistamine) and antagonist (thioperamide) of H3-receptors were developed. Results from a number of studies indicate a variety of physiological roles of neuronal histamine such as thermoregulation, feeding behavior, sexual activity, sleep-wakefulness cycle, hormonal regulation and so on. Moreover, histaminergic drugs affect not only the emotional behavior, but also are effective to treat some patients of depression, Parkinson's disease, akathisia, motion sickness and so on. The central histaminergic neuron system is also affected by mental disorders and neuropsychopharmacological drugs. This review especially focused on these points and suggests that the central histaminergic neuron system may play an important role in the regulation of mental functions.
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PMID:[Recent advances in neuropsychopharmacology of the central histaminergic neuron system]. 192 57

Neurotransmitters and neuromodulators involved in the function of vestibular nuclei were reviewed with special reference to drugs used for treatment of motion sickness and vertigo. Biochemical, histochemical and electrophysiological studies have demonstrated that acetylcholine is a transmitter candidate from the afferent vestibular nerve to the lateral vestibular nucleus (LVN), because acetylcholine satisfies most criteria for a chemical transmitter in the central nervous system. It is unlikely, however, that monoamines such as noradrenaline, dopamine and serotonin are transmitters in the vestibular neurons, since cell bodies and nerve terminals containing the monoamines have not been detected yet in the vestibular nuclei. Although histamine and H1-receptor blockers inhibit neuron activities in the vestibular nuclei, it is unclear at present whether histaminergic system is directly related to the function of vestibular neurons. It has been established that GABA is an inhibitory transmitter from the cerebellar Purkinje cells to the LVN neurons. Diazepam is considered to enhance the GABA effect on the LVN, thereby modifying the vestibular neuronal firing. Enkephalin-containing cell bodies and nerve terminals are found in the medial vestibular nucleus, and a few substance P-containing neurons have been observed in the vestibular nuclei. However, the functional role of these peptides on the vestibular system remains to be determined. Unlike histamine H1-receptor blockers, vasodilators such as cinnarizine, ifenprodil and adenosine triphosphate, which are effective in treatment of vertigo, produce an enhancement of responsiveness of neuron activities in the vestibular nuclei, probably as a result of an increase in blood flow in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Experimental vestibular pharmacology: a minireview with special reference to neuroactive substances and antivertigo drugs. 639 58

Despite important advances in pharmacotherapeutic options for the prevention and treatment of nausea and vomiting during the 1990s, a significant proportion of patients still suffer debilitating nausea and vomiting symptoms. The most problematic areas are chemotherapy-induced nausea and vomiting particularly delayed emesis, postoperative nausea and vomiting, opioid-induced nausea and vomiting and motion sickness. The most vigorous research into new anti-emetics has focused on the neurokinin-1 (substance P) antagonists. Clinical trials conducted to date indicate that these agents have similar efficacy to 5-HT(3) antagonists in acute chemotherapy-induced nausea and vomiting, superior efficacy to available agents in delayed emesis, possibly superior efficacy against emesis in postoperative nausea and vomiting and no evidence of efficacy versus opioid or motion-induced nausea and vomiting. Other pharmacological strategies in development include agonising CB1 (cannabinoid) receptors, "broad spectrum" receptor antagonists and 5-HT(1A) receptor agonists, although clinical trials of these types of agents are not yet available. The neurokinin-1 antagonists appear to be promising agents for some nausea and vomiting states, although further clarification of their role is required.
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PMID:Anti-emetics in development. 1203 23

Ginger (rhizomes of Zingiber officinale) has been shown to exert potent anti-emetic properties, but its mode of action has not yet been elucidated. Among its active constituents, [6]-, [8]- and [10]-gingerol as well as [6]-shogaol were shown in different in vivo studies to be at least partly responsible for the drug's anti-emetic properties. In an attempt to gain more insight into the mode of action of these compounds, three different in vitro models were used to investigate their effects on 5-HT(3) receptors (serotonin receptor subtype) in more detail: [(14)C]guanidinium influx into N1E-115 cells which express 5-HT(3) receptors, isotonic contractions of the isolated guinea-pig ileum and equilibrium competition binding studies using a radioactively labeled 5-HT(3) receptor antagonist ([(3)H]GR65630) (3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone). All four compounds inhibited the [(14)C]guanidinium influx through 5-HT(3) receptor channels as well as contractions of the guinea-pig ileum induced by SR57227A ((4-amino)-(6-chloro-2-pyridyl)l-piperidine hydrochloride), a highly selective 5-HT(3) receptor agonist. Both effects were concentration-dependent, with the following order of potency for both models: [6]-shogaol> or =[8]-gingerol>[10]-gingerol> or =[6]-gingerol. All compounds showed also weak anticholinergic and antineurokininergic activities in the guinea-pig ileum (acetylcholine and substance P are mediators of the 5-HT(3) receptor effect). The vanilloid receptor did not seem to be involved derived from experiments using capsazepine. None of the tested ginger substances, however, was able to displace [(3)H]GR65630 from its binding site (5-HT(3) receptor) neither on intact N1E-115 cells nor on the purified membranes of HEK-293 cells over-expressing the h5-HT(3) receptor. It may be concluded that [6]-, [8]-, [10]-gingerol and [6]-shogaol exert their anti-emetic effect at least partly by acting on the 5-HT(3) receptor ion-channel complex, probably by binding to a modulatory site distinct from the serotonin binding site. This may include indirect effects via receptors in the signal cascade behind the 5-HT(3) receptor channel complex such as substance P receptors and muscarinic receptors; this needs further investigation since ginger is effective against motion sickness which is cured by some vanilloids and by anticholinergics such as scopolamine.
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PMID:Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum. 1636 90

We previously reported that motion sickness was prevented in rats with amygdala lesion and that provocative motion stimuli increased the number of Fos-positive neurons in the amygdala, suggesting that the amygdala is one of the neural substrates involved in the development of motion sickness. NK-1 receptors in the brain stem and amygdala are thought to play an important role in emesis and affective disorders, respectively. In the present study, to elucidate a role of substance P neuronal system and NK-1 receptors in the brain stem and amygdala in the development of motion sickness, we measured changes in gene expression of NK-1 receptors and preprotachykinin, a precursor of substance P, using quantitative real-time PCR methods in solitary tract nucleus and amygdala in rats after provocative motion stimuli induced by 2G hypergravity load. Effects of systemic administration of CP-99,994, an antagonist for NK-1 receptors, on hypergravity-induced motion sickness were also examined using pica behavior, eating non-nutritive substances such as kaolin, as an index of motion sickness in rats. Hypergravity-induced motion sickness was inhibited by CP-99,994 with a dose-dependent and enantioselective manner. Preprotachykinin mRNA expression was increased in basolateral nucleus of amygdala and solitary tract nucleus after hypergravity load for 3h, whereas NK-1 receptor mRNA expression was not changed by hypergravity in amygdala and solitary tract nucleus. Present results suggest that 2G hypergravity load activated the substance P neuronal system in amygdala as well as in the brain stem and this activation would be related to the development of motion sickness.
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PMID:Implication of substance P neuronal system in the amygdala as a possible mechanism for hypergravity-induced motion sickness. 2219 10

Postoperative nausea and vomiting (PONV) can be very debilitating for surgical patients, and effective management reduces potential morbidity, aiding in patient satisfaction, and minimizing the need for unintended hospital stays. Risk factors include female sex, nonsmoker, and having a previous history of motion sickness or PONV. Anesthetic risk factors include receiving opioids, not receiving a total intravenous anesthetic (TIVA), exposure to nitrous oxide, and extended length of anesthetic. Many treatments, including serotonin antagonists, dopamine antagonists, corticosteroids, inhaled isopropyl alcohol, and anticholinergics, as well as techniques such as TIVA, have been utilized over recent decades in an attempt to reduce PONV incidence. However, it remains a problem for a significant number of surgical patients. Aprepitant is a neurokinin-1 (substance P) antagonist, which exerts its effects via a final common pathway of the emetic centers after crossing the blood brain barrier. Aprepitant is commonly used in the cancer population to help prevent cancer chemotherapy-induced nausea and vomiting and has shown great promise in both acute and delayed phase PONV. Published data has shown improved efficacy when compared with ondansetron administered prior to surgery. The use of aprepitant in combination with other antiemetics potentially may help decrease unplanned hospital admissions and potentially, reduce costs associated with PONV.
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PMID:The role of neurokinin-1 (substance P) antagonists in the prevention of postoperative nausea and vomiting. 2941 32

Neurokinin-1 (NK-1) receptors are present in both the central nervous system and peripheral tissues. Substance P (SP) is the major ligand and is involved in multiple processes including pain transmission, vasodilation, modulation of the inflammatory response, as well as the sensory neuronal transmission involved in stress, anxiety, and emesis. The involvement of NK-1 and SP in the vomiting reflex has led to the development of NK-1 antagonists to prevent and treat vomiting in human and veterinary medicine. Maropitant is a potent, selective neurokinin (NK-1) receptor antagonist that blocks the pharmacologic action of SP in the central nervous system. Maropitant is available in both an injectable and tablet formulation and approved for use in dogs and cats for the treatment and prevention of vomiting from a variety of clinical causes and motion sickness. When administered prior to anesthetic premedication, maropitant prevents or significantly decreases the incidence of opioid-induced vomiting and signs of nausea in dogs and cats. Maropitant has also been shown to improve postoperative return to feeding and food intake in dogs. The minimum alveolar concentration of sevoflurage is decreased in both dogs and cats by maropitant, indicating a potential role as an adjunct analgesic, especially for visceral pain. This article will review the background information and literature, including clinical recommendations with respect to the perioperative use of maropitant in canine and feline veterinary patients.
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PMID:Spotlight on the perioperative use of maropitant citrate. 3005 Aug 55

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists-originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists-searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H1) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists-investigations of their pharmacology as "sedatives" (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D2) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine3(5-HT3) receptor antagonists-metoclopramide was initially assumed to act only via D2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine4 receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT3 receptors. The latter led to identification of selective 5-HT3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin1receptor antagonists-antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years.
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PMID:A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research. 3023 61

Introduction: Novel therapies are needed for the treatment of motion sickness given the inadequate relief and bothersome and dangerous adverse effects of currently approved therapies. Neurokinin-1 (NK1) receptor antagonists have the potential to be effective in improving the symptoms of motion sickness, given the involvement of Substance P in nauseogenic and emetic pathways and the expression of NK1 receptors in the gastrointestinal system. Here we evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness in variable sea conditions. Methods: A total of 126 adults participated in the Motion Sifnos study. Groups of participants were assigned to one of seven boat trips lasting ~4 h on the Pacific Ocean. Participants were randomized 1:1 to tradipitant 170 mg or placebo and completed the Motion Sickness Severity Scale (MSSS) every 30 min, in addition to other assessments. Severity of motion sickness was assessed with the incidence of vomiting and the MSSS. Results: Participants on tradipitant had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant = 17.5%, placebo = 39.7%, p = 0.0039). For trips exposed to rough sea conditions, the difference in the incidence of vomiting between the groups was more dramatic (tradipitant = 15.79%, placebo = 72.22%, p = 0.0009). Across these trips, motion sickness symptoms were significantly lower in the tradipitant group compared to the placebo group (tradipitant = 3.19, placebo = 4.57, p = 0.0235). Discussion: Tradipitant has the potential to be an effective therapy for the prevention of vomiting and treatment of nausea in people with motion sickness.
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PMID:Tradipitant in the Treatment of Motion Sickness: A Randomized, Double-Blind, Placebo-Controlled Study. 3311 60