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

The stress-induced hyperthermia test is a paradigm developed several years ago to model the expression of autonomic hyperactivity in anxiety. Whereas in the classical stress-induced hyperthermia, cohort removal was used, in a recently described modification of the stress-induced hyperthermia model singly housed mice rather than groups of mice were used. The modification of this model can be summarized as follows: rectal temperature is recorded in singly housed animals at two consecutive time-points (T1 and T2) which are interspaced by a defined time-interval (15 min). Since the value at the second temperature-recording exceeds the value of the initial measure it is the difference between these two core-temperatures which reflects stress-induced hyperthermia. In the present study, the stress-induced hyperthermia paradigm, in its modified design, was evaluated in OF1/IC mice. By comparing the effect of various compounds in both the modified as well as the classical (cohort removal) stress-induced hyperthermia paradigm, a very high correlation was found for the pharmacological sensitivity of the two paradigms. Furthermore, it was demonstrated that other anxiolytics, all known to be active in the classical stress-induced hyperthermia paradigm, such as the benzodiazepines chlordiazepoxide (0.3, 1, 3, 10 mg/kg, p.o.), diazepam (0.1, 0.3, 1, 3 mg/kg, p.o.), clobazam (5 or 10 mg/kg, p.o.) and oxazepam (5 or 10 mg/kg, p.o.) as well as the non-benzodiazepines buspirone (7.5 or 15 mg/kg, p.o.) and ethanol (15% or 30%, 10 ml/kg, p.o.), showed a marked reduction in stress-induced hyperthermia in the modified design. New candidate anxiolytics, i.e. the metabotropic glutamate (mGlu) receptor group 2 agonist LY314582 (1 or 10 mg/kg, p.o.; racemic mixture of LY354740 ((2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid), the metabotropic glutamate 5 receptor antagonist MPEP (1, 7.5, 15 or 30 mg/kg, p.o.; 2-methyl-6-(phenylethynyl)pyridine) and the neurokinin 1 (NK1) receptor antagonist NKP608 (0.01 or 0.1 mg/kg, p.o.; quinoline-4-carboxylic acid [trans-(2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-amide) also reduced stress-induced hyperthermia in the modified paradigm clearly indicating anxiolytic-like activity for these compounds. Finally, the effects of the classical benzodiazepine chlordiazepoxide (10 mg/kg, p.o.), in parallel with its effect on stress-induced hyperthermia, were also investigated for its effect on plasma concentrations of the two stress hormones, adrenocorticotropin (ACTH) and corticosterone. It was shown that all three parameters were significantly increased 15 min after T1 in vehicle-treated mice whereas the increase was significantly attenuated following pre-treatment with chlordiazepoxide. In conclusion, all the data presented here indicate that the modified version of the stress-induced hyperthermia-paradigm is a valid and interesting alternative to the classical stress-induced hyperthermia test.
 ...
PMID:Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608). 1182 Oct 22

The influence of central substance P (SP) administration on alcohol intake and brain dopamine metabolism within mesocortico-limbic and nigrostiatal systems of rats exposed to ethanol, was studied. During 6 months, the rats consumed 15% ethanol solution instead of water. Central administration of SP (3 mcg/kg) decreased alcohol consumption by 41% in alcohol-preference animals. After long-term ethanol exposure ratios DOPAC/DA and HVA/DA were reduced in striatum and accumbens. SP in dose 3 mcg/kg increased content of DOPAC by 17% and HVA by 23% as well as DOPAC/DA by 9%, HVA/DA by 19% in accumbens. Whereas in striatum only increased DOPAC (28%) and HVA (29%) were observed as compared with saline-treated rats.
 ...
PMID:[The influence of substance P central administration on ethanol intake in rats chronically exposed to alcohol]. 1223 60

The mechanisms by which transforming growth factor-a (TGP-alpha) protects the stomach against mucosal injury are incompletely understood. The aim of this study was to examine the roles of sensory neurons, sensory neuropeptides and prostaglandins in TGFalpha gastroprotection against ethanol. Fasted rats received TGF-alpha (50 microg/kg, intraperitoneally) prior to orogastric ethanol (75% v/v, 1 ml). Gastric injury was quantitated 30 min after ethanol. Involvement of sensory neurons and the sensory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), were examined by capsaicin deafferentation and specific receptor antagonist infusion, respectively. Indomethacin (10 mg, intragastrically) was used to determine the role of prostaglandins in TGF-alpha-mediated gastroprotection. TGF-alpha significantly diminished ethanol-induced gastric lesion area to 5.7 +/- 0.8 mm2 vs 41.1 +/- 5.2 mm2 (p < 0.001). Sensory denervation and CGRP-receptor blockade abolished the TGF-alpha protective effect. In contrast, SP antagonist and indomethacin did not alter TGF-alpha gastroprotection. In conclusion, TGF-alpha-mediated gastroprotection involves sensory neuron activation and CGRP release and this protective effect did not involve substance P or prostaglandin generation.
 ...
PMID:Mechanisms of transforming growth factor-alpha (TGF-alpha) induced gastroprotection against ethanol in the rat: roles of sensory neurons, sensory neuropeptides, and prostaglandins. 1264 11

The binding of 125I-labeled substance P (SP) to rat brain cortex membranes has been studied under control conditions and in the presence of ethanol. The binding of SP at low concentrations (20-1000 pM) gave two components, one with a KD value of 80 pM and another one with a KD of 500 pM. The higher-affinity component is due to NK1 receptors, as confirmed by the inhibition of the SP binding by the rodent NK1 specific agonist [Sar9 Met(O2)11]SP. Ethanol (1.7 mM) added to the binding assays inhibited by more than 50% the specific binding at a very low SP concentration (20 pM); however, it had no effect at SP concentrations ranging from 50 to 120 pM. This suggests a decrease by ethanol of the affinity of SP to the NK1 receptors involved in this binding component. The ethanol effect disappeared at [EtOH] < or = 0.17 mM.
 ...
PMID:Ethanol inhibits the binding of substance P to rat brain cortex NK1 receptors. 1283 54

Peripheral tachykinins (TKs) are believed to play a role in the pathogenesis of inflammatory bowel diseases (IBD). In this study we investigated changes induced by central administration of two natural TK receptor agonists, NK(1) (PG-SPI) and NK(3) (PG-KII), on trinitrobenzene sulphonic acid (TNBS)- and dextran sodium sulphate (DSS)-induced experimental colitis in rats. Colitis was induced by instilling a single intracolonic dose of TNBS 50 mgkg(-1) (0.5 ml in 50% ethanol) or by oral administration of 5% DSS for 7 days. Each group of rats was intracerebroventricularly injected daily with PG-SPI and PG-KII (0.5, 5, and 50 microgkg(-1)). On day 3, TNBS-treated animals were killed and the severity of gut inflammation was evaluated by measuring myeloperoxidase (MPO) activity, interleukin-1beta (IL-1beta) production and by scoring macroscopic and histologic colonic damage. DSS-treated animals were checked daily for the length of survival and for stool consistency and faecal blood. In the TNBS group, PG-SPI and PG-KII increased scores for the severity of colonic damage, stimulated the production of IL-1beta and increased granulocyte infiltration into the colon (MPO activity). In the DSS group, PG-SPI and PG-KII decreased the percentage of surviving animals, and increased the number of rats that developed loose stools and blood in the faeces and the MPO activity. These results indicate that centrally injected NK(1) and NK(3) tachykinin receptor agonists play a proinflammatory role in experimentally-induced colitis in rats.
 ...
PMID:Central effects of selective NK1 and NK3 tachykinin receptor agonists on two models of experimentally-induced colitis in rats. 1294 43

A capsaicin-like endogenous ligand of vanilloid (VR1) receptors, N-arachidonoyl-dopamine, was recently identified in bovine and rat nervous tissue, and found to be almost as potent as capsaicin, and 5-10-fold more potent than anandamide, on these receptors, both in isolated cells and in vivo. Here we have investigated if N-arachidonoyl-dopamine also exerts other capsaicin-like effects at VR1 receptors in some isolated organ preparations. N-arachidonoyl-dopamine exerted a potent contractile response of guinea pig isolated bronchi (EC50=12.6 +/- 1.7 microM, Emax=69.2 +/- 2.4% of carbachol Emax), which was blocked by pre-treatment with capsaicin or with the VR1 antagonist capsazepine, as well as by a combination of tachykinin NK1 and NK2 receptor antagonists. In this assay, N-arachidonoyl-dopamine was less and more potent and/or efficacious than capsaicin (EC50=40.0 nM; Emax=93.5%) and anandamide (EC50=15.2 microM, Emax=38.0%), respectively. Unlike capsaicin and anandamide, forskolin or ethanol did not enhance N-arachidonoyl-dopamine effect in this preparation, whereas epithelial denudation resulted in a 2.5-fold increase in potency without affecting the efficacy. N-arachidonoyl-dopamine also contracted the isolated guinea pig urinary bladder, although in this preparation, as well as in the isolated rat urinary bladder, the potency (EC50=3.7 +/- 0.3 and 19.9 +/- 0.1 microM) and/or efficacy (Emax=12.0 +/- 0.1% and 20.7 +/- 0.7% of carbachol Emax) of the compound were significantly lower than those of both capsaicin and anandamide. These data suggest that the extent to which exogenous N-arachidonoyl-dopamine activates VR1 receptor in isolated organs is largely dependent on pharmacodynamics and bioavailability.
 ...
PMID:Capsaicin-like effects of N-arachidonoyl-dopamine in the isolated guinea pig bronchi and urinary bladder. 1295 66

The enzyme and binding protein dipeptidyl peptidase IV (DPPIV/CD26) has a unique enzymatic specificity in cleaving dipeptides from neuropeptides, chemokines, and hormones. Thus, DPPIV is potentially involved in the regulation of functions of the immune, endocrine, and nervous systems. In the present study, we compared DPPIV-deficient, mutant Japanese [F344/DuCrj(DPPIV-)] and German [F344/Crl(Ger/DPPIV-)] F344 rat substrains with a wild-type-like F344 substrain [F344/Crl(Por)] from the United States in a multitiered strategy using a number of different behavioral tests. General health, neurological and motor functions, and sensory abilities of the different F344 substrains were not different. A reduced body weight and a reduced water consumption were observed in mutant animals. DPPIV-deficient rats exhibited increased pain sensitivity in a non-habituated hot plate test, indicative of a reduced stress-induced analgesia. In line with this finding, reduced stress-like responses in tasks like the open field (OF), social interaction (SI), and passive avoidance test were found. Differences in DPPIV-like activity appear to be involved in neurophysiological processes because DPPIV-deficient animals were less susceptible to the sedative effects of ethanol. The varying phenotypes of the F344 substrains are likely to be mediated by differential degradation of DPPIV substrates such as substance P, glucagon-like peptide (GLP)-1, enterostatin, and especially neuropeptide Y (NPY). Potentially, DPPIV-deficient substrains represent an important tool for biomedical research, focusing on the involvement of DPPIV and its substrates in behavioral and physiological processes.
 ...
PMID:Extreme reduction of dipeptidyl peptidase IV activity in F344 rat substrains is associated with various behavioral differences. 1456 17

Ethanol (EtOH) stimulates peptidergic primary sensory neurons via the activation of the transient receptor potential vanilloid-1 (TRPV1). EtOH is also known to trigger attacks of asthma in susceptible individuals. Our aim was to investigate whether EtOH produces airway inflammation via a TRPV1-dependent mechanism and to verify whether this effect is produced via a mechanism distinct from that of acetaldehyde (AcH). EtOH caused a Ca(2+)-dependent release of neuropeptides from guinea pigs airways, an effect that was inhibited by both capsaicin pretreatment and the TRPV1 antagonist capsazepine (CPZ). Furthermore, EtOH contracted isolated guinea pig bronchi, showing efficacy similar to that of carbachol: this effect of EtOH was sensitive to capsaicin pretreatment, tachykinin receptor blockade, and TRPV1 antagonism. The EtOH metabolite AcH also contracted isolated guinea pig bronchi, but this action was not affected by capsaicin pretreatment, tachykinin receptor, or TRPV1 antagonism. EtOH by intravenous or intragastric route of administration caused bronchoconstriction and increased plasma extravasation in the guinea pig airways, effects that were abolished selectively by CPZ. In conclusion, we have demonstrated that EtOH stimulates peptidergic primary sensory neurons in the guinea pig airways by TRPV1 activation. This excitatory effect of EtOH, distinct from that of AcH, results in neurogenic inflammatory responses that may contribute to the mechanism of EtOH-induced asthma.
 ...
PMID:Ethanol causes inflammation in the airways by a neurogenic and TRPV1-dependent mechanism. 1476 3

The effects of central administration of substance P (SP) on alcohol consumption and dopamine metabolism in the projections of the mesocorticolimbic and nigrostriatal systems of the brain were studied in chronically alcoholic rats. Rats received 15% ethanol solution for 6 months without choice. Intraventricular administration of SP (1 microg/rat) decreased consumption of 10% ethanol solution by 41% compared with controls in an alcohol free choice test lasting one day. After chronic alcoholism, there was a decrease in the ratio of dihydroxyphenylacetic acid (DOPA) and homovanillic acid (HVA) to dopamine in the nucleus accumbens and striatum in rats subjected to alcoholism, as compared with intact controls. Chronically alcoholic rats treated with SP showed increases in DOPA, HVA, and the DOPA:dopamine and HVA:dopamine ratios in the nucleus accumbens as compared with animals given physiological saline, by 17%, 23%, 9% and 19% respectively. The only increases in the striatum were in the absolute levels of DOPA and HVA, by 28% and 29%, while the ratios of these metabolites to dopamine remained unchanged. Thus, central administration of SP decreased the voluntary consumption of ethanol in the ethanol free choice test and enhanced dopamine metabolism in structures of the mesolimbic and nigrostriatal systems in chronically alcoholic rats.
 ...
PMID:Mechanisms of the influences of the central administration of substance P on ethanol consumption in chronically alcoholic rats. 1496 30

Substance P is readily expressed in skin inflammatory disorders such as psoriasis and contact dermatitis. Spantide II is a peptide (MW 1668.76) that specifically binds to neurokinin-1 receptor (NKR-1) and blocks inflammation associated with substance P. The anti-inflammatory property of Spantide II makes it a suitable candidate to be studied as a topical formulation for the treatment of dermal inflammatory disorders. The objective of this study was to investigate the influence of pH, temperature, salt concentration and concentration on the aqueous stability of Spantide II. The stability of Spantide II was also assessed by circular dichroic (CD) spectroscopy and mass spectrometry (MS). The influence of various dermatological vehicles (ethanol, Transcutol, propylene glycol, N-methyl-2-pyrrolidone (NMP), ethyl oleate, isopropyl myristate and laurogylcol FCC (LFCC)) on the stability of Spantide II was investigated. A precise high-performance liquid chromatography (HPLC) assay was developed for analysis of Spantide II. At higher temperature (40 degrees C) the stability of Spantide II decreased with increase in pH (P < 0.05). Change in salt concentration did not appreciably affect the stability of Spantide II (P > 0.05). The concentration of Spantide II in the solution had no significant influence on its stability (P > 0.05). CD spectroscopy studies showed that Spantide II has a relatively stable alpha-helix structure in the liquid state. The stability of Spantide II was affected by the type of vehicle used in the study (P < 0.01) at different temperatures (P < 0.05). Spantide II at high temperature undergoes lysine-proline diketopiperazine degradation as evident in MS data. Spantide II was relatively more stable in ethyl oleate-ethanol, ethanol-water, ethanol and N-methyl-2-pyrrolidone. The results of this study indicate that ethyl oleate-ethanol (1:1) and ethanol-water (1:1) could be used as potential vehicles in the development of topical formulations of Spantide II.
 ...
PMID:Preformulation stability of Spantide II, a promising topical anti-inflammatory agent for the treatment of psoriasis and contact dermatitis. 1497 97


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>