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)

This review summarizes recent findings of our laboratory that have been directed at: (1) identifying the neural circuits underlying the expression and modulation of defensive rage behavior in the cat and the neurotransmitters associated with these pathways; and (2) determining which components of the circuitry are affected by alcohol administration and which significantly alter the rage mechanism. The experiments described herein incorporated a number of converging methods, which include brain stimulation, behavioral pharmacology, immunocytochemistry, retrograde tract tracing and receptor binding. For behavioral pharmacological studies, monopolar electrodes and cannula-electrodes were implanted into selected regions along the limbic-midbrain axis for electrical stimulation and local microinfusion of drugs. The findings demonstrated: (1) a direct pathway from the anterior medial hypothalamus to the dorsal periaqueductal gray (PAG) over which this response is mediated. This pathway utilizes excitatory amino acids that act upon NMDA receptors within the midbrain PAG; (2) that the region of the dorsal PAG, from which defensive rage could be elicited, receives other inputs from the basal amygdala that facilitate this response by acting upon NMDA receptors; (3) a pathway from the medial amygdala to the medial hypothalamus that also facilitates defensive rage and whose functions are mediated by substance P receptors within the medial hypothalamus; (4) that the PAG also receives enkephalinergic inputs from the central nucleus of amygdala, which act upon mu receptors, and which powerfully suppress defensive rage; and (5) that recent findings reveal that ethanol administration facilitates defensive rage by virtue of its interactions with the medial hypothalamus, its descending projection to the PAG, and possibly with NMDA receptors within this pathway.
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PMID:Neurotransmitters regulating defensive rage behavior in the cat. 941 98

Inflammation suppresses phasic contractile activity in vivo. We investigated whether inflammation also suppresses in vitro phasic contractile activity and, if so, whether this could in part be due to the alteration of specific slow wave characteristics and morphology of the interstitial cells of Cajal (ICC). Circular muscle strips were obtained from normal and inflamed distal canine colon. Inflammation was induced by mucosal exposure to ethanol and acetic acid. The amplitudes of spontaneous, methacholine-induced, substance P-induced, and electrical field stimulation-induced contractions were smaller in inflamed muscle strips than in normal muscle strips. Inflammation reduced the resting membrane potential and the amplitude and duration of slow waves in circular muscle cells. Inflammation did not affect the amplitude of inhibitory junction potentials but did decrease their duration. Ultrastructural studies showed expansion of the extracellular space between circular muscle cells, reduction in the density of ICC and associated neural structures, damage to ICC processes, vacuolization of their cytoplasm, and blebbings of the plasma membrane. We conclude that inflammation-induced alterations of slow wave characteristics contribute to the suppression of phasic contractions. These alterations may, in part, be due to the damage to ICC. Inflammation impairs both the myogenic and neural regulation of phasic contractions.
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PMID:Inflammation modulates in vitro colonic myoelectric and contractile activity and interstitial cells of Cajal. 943 48

Ethyl alcohol has many symptomatic effects on the gastrointestinal tract. Our aim was to determine the effects of ethyl alcohol on circular smooth muscle contractility of the canine small bowel. Mechanical and intracellular electrical recordings were made in vitro from the circular muscle of full-thickness strips of muscularis externa from canine jejunum. Ethyl alcohol (20-120 mM) dose-dependently decreased spontaneous contractile amplitude, hyperpolarized the resting membrane potential, and decreased the amplitude of the slow wave. Ethyl alcohol also decreased the amplitude of the inhibitory junction potential (during electrical field stimulation-EFS) but did not alter the maximum absolute cell-polarized potential reached during EFS. An increase in extracellular calcium (15 mM) partially restored spontaneous contractile amplitude, resting membrane potential, and slow-wave amplitude. Ethyl alcohol decreased the amplitude of contractions evoked by acetylcholine, CCK, and substance P. These data suggest that ethyl alcohol has direct effects on jejunal smooth muscle contractility. These effects can be partially reversed by increasing the availability of extracellular calcium.
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PMID:Effects of ethyl alcohol on canine jejunal circular smooth muscle. 944 Jun 12

Since exogenously applied tachykinins (substance P and neurokinin A) prevent the neurogenic hyperaemia which is elicited by acid back-diffusion in the rat stomach, we investigated whether endogenous tachykinins would act in a similar manner. Acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCI, increased gastric mucosal blood flow (GMBF) by 60-100% as determined by hydrogen clearance in urethane-anaesthetized rats. This response remained unchanged after pretreatment with the tachykinin NK1 receptor antagonist SR 140,333 (300 nmol/kg) but tended to be enhanced by the NK2 receptor antagonist MEN 10,627 (200 nmol/kg). When given during ongoing acid back-diffusion, MEN 10,627 significantly enhanced the acid-evoked vasodilatation as compared with vehicle or SR 140,333. We conclude that endogenously released tachykinins, acting via NK2 receptors, limit the gastric hyperaemic response to acid.
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PMID:Inhibition of acid-induced hyperaemia in the rat stomach by endogenous NK2 receptor ligands. 945 33

It is established that dopamine (DA) controls the expression of preprodynorphin (PPDYN), preprotachykinin A (PPT-A) and preproenkephalin (PPE) mRNAs in striatal structures. Since cocaine, nicotine and ethanol enhance extracellular DA concentration, we have examined whether their repeated administration produced common changes in the expression of these mRNAs. Quantitative in situ hybridization histochemistry was performed in rats 2 h after a final challenge subsequent to repeated subcutaneous injections (3 X a day) of cocaine (12.5 mg/kg), nicotine (0.4 mg/kg) for 14 days and ethanol (160 mg/kg) for 7 days. In the dorsal striatum, cocaine produced simultaneous PPDYN and PPT-A mRNA increases without PPE mRNA change whereas nicotine and ethanol produced no modification. After cocaine, PPDYN mRNA was preferentially increased in striatal patch compartment. In the nucleus accumbens, the effects were more complex. In cocaine-treated rats, we measured concomitant increases of PPDYN and PPE mRNA in the rostral pole, an isolated induction of PPT-A mRNA signals in the core without any change in the two shell subregions: the cone and the ventral shell. In contrast, after nicotine and ethanol, the ventral shell was the only accumbal subregion which showed a neuropeptide mRNA alteration, nicotine leading to decreased PPDYN mRNA and ethanol to increased PPT-A mRNA contents. The neuropeptide regulation after chronic treatment with these psychostimulant drugs does not strictly conform to a general DA control scheme in the dorsal and the ventral striatum. The cocaine effects can be clearly distinguished from those of nicotine and ethanol in terms of neuropeptide regulation and striatal subregions affected.
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PMID:Repeated administration of cocaine, nicotine and ethanol: effects on preprodynorphin, preprotachykinin A and preproenkephalin mRNA expression in the dorsal and the ventral striatum of the rat. 952 67

In [3H]myristic acid-prelabeled Chinese hamster ovary cells stably expressing the rat NK1 tachykinin receptor, the selective NK1 agonist [Pro9]substance P ([Pro9]SP) time and concentration dependently stimulated the formation of [3H]phosphatidylethanol in the presence of ethanol. This [Pro9]SP-induced activation of phospholipase D (PLD) was blocked by NK1 receptor antagonists and poorly or not mimicked by NK2 and NK3 agonists, respectively. In confirmation of previous observations, [Pro9]SP also stimulated the hydrolysis of phosphoinositides, the release of arachidonic acid, and the formation of cyclic AMP (cAMP). All these [Pro9]SP-evoked responses could be mimicked by aluminum fluoride, but they remained unaffected in cells pretreated with pertussis toxin, suggesting that a Gi/Go protein is not involved in these different signaling pathways. The activation of PLD by [Pro9]SP was sensitive to external calcium and required an active protein kinase C because the inhibition of this kinase (Ro 31-8220) or its down-regulation (long-term treatment with a phorbol ester) abolished the response. In contrast, a cAMP-dependent process was not involved in the activation of PLD because the [Pro9]SP-evoked response was neither affected by Rp-8-bromoadenosine 3',5'-cyclic monophosphorothioate nor mimicked by cAMP-generating compounds (cholera toxin or forskolin) or by 8-bromo-cyclic AMP. A functional coupling of NK1 receptors to PLD was also demonstrated in the human astrocytoma cell line U 373 MG stimulated by SP or [Pro9]SP. These results suggest that PLD activation could be an additional signaling pathway involved in the mechanism of action of SP in target cells expressing NK1 receptors.
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PMID:Functional coupling of the NK1 tachykinin receptor to phospholipase D in chinese hamster ovary cells and astrocytoma cells. 957 95

The present study evaluated the sensitivity of several brain sites to the inhibitory effect of the tachykinin (TK) NK-3 receptor agonist aminosenktide (NH2-SENK) on 10% ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring rats. Attention was focused on limbic structures involved in alcohol-seeking behavior and endowed with TK NK-3 receptors. NH2-SENK was bilaterally injected into the shell of the nucleus accumbens (NACC), the medial amygdala (AMY), the dorsal hippocampus (HIPP), the ventral tegmental area (VTA), the bed nucleus of the stria terminalis (BNST), the lateral hypothalamus (LH), and the nucleus basalis magnocellularis (NBM). NH2-SENK (injected up to 25-75 ng/site) into the NACC, AMY, HIPP, and VTA did not significantly modify ethanol intake. Injection of NH2-SENK into the BNST reduced ethanol intake at doses of 25 ng/site or higher, but the same doses also reduced water intake in water-deprived rats and food intake in food-deprived rats. Injection of NH2-SENK into the LH or the NBM at doses of 0.5, 5, or 25 ng/site inhibited 10% ethanol intake even at the lowest dose tested without affecting either food or water consumption in deprived animals. Present results indicate that the LH and the NBM are highly sensitive to the inhibitory effect of the TK NK-3 receptor agonist NH2-SENK on ethanol intake. TK peptides have been shown to evoke conditioned place preference following injection in the LH or the NBM, suggesting that in these brain sites the effect of TK agonists on ethanol intake might be due to interference with reward processes.
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PMID:Sensitivity of brain sites to the inhibitory effect on alcohol intake of the tachykinin aminosenktide. 966 56

Previous studies have shown tachykinins implicated in gut inflammation. The aim of this work was to evaluate the effect of treatments with tachykinin NK1, NK2, and NK3 selective receptor antagonists on the development of gut inflammation induced by trinitrobenzenesulfonic acid (TNBS) in rats and guinea-pigs. On day 0, rats and guinea-pigs received an intraluminal instillation of TNBS/ethanol (40 mg/kg). Each group was daily treated with intraperitoneally injected NK1 (SR 140333; 0.3 mg/kg/day), NK2 (SR 48968; 5 mg/kg/day), or NK3 (SR 142801; 1, 5, or 10 mg/kg/day) receptor antagonists or their vehicle. On day 4, inflammatory levels were evaluated by measuring gut permeability, myeloperoxidase activity, macro- and microscopic damage scores. In TNBS treated rats, daily administration of SR 140333 (0.3 mg/kg/day) and SR 48968 (5 mg/kg/day) reduced colonic inflammation. In TNBS treated guinea-pigs, daily administration of SR 48968 (5 mg/kg/day) and SR 142801 (at 5 and 10 mg/kg/day) attenuated significantly ileal injury. These results suggest that non-peptide tachykinin receptor antagonists are potent anti-inflammatory agents on gut inflammation in rats and guinea-pigs. However, their activity depends upon the animal species and type of receptor considered.
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PMID:Comparative effects of nonpeptide tachykinin receptor antagonists on experimental gut inflammation in rats and guinea-pigs. 969 38

Intracerebroventricular (i.c.v.) injection of tachykinin (TK) NK-3 receptor agonists inhibits alcohol intake in genetically selected alcohol-preferring rats. The present study investigated the mechanism of action by which the selective TK NK-3 receptor agonist aminosenktide (NH2-SENK) attenuates ethanol intake in Marchigian Sardinian alcohol-preferring (msP) rats. The effect of NH2-SENK was studied by i.c.v. injection in the conditioned taste aversion (CTA) and in the conditioned place preference (CPP) paradigms; moreover, the effect of NH2-SENK on blood alcohol levels (BAL) following intragastric ethanol administration was investigated. The i.c.v. dose of 125 ng/rat of NH2-SENK, that markedly reduces ethanol intake, did not modify BAL, nor did it increase the CTA induced by intraperitoneal injection of ethanol, 1 g/kg body weight. These findings suggest that the effect of NH2-SENK on alcohol consumption is not related to modification of the pharmacokinetics of ethanol, nor to increase of the aversive properties of ethanol. On the other hand, the same i.c.v. dose of NH2-SENK evoked a pronounced and statistically significant CPP. This finding indicates that the TK NK-3 receptor agonist NH2-SENK possesses rewarding properties in msP rats and suggests that its inhibitory effect on ethanol consumption may be due to substitution of the rewarding properties of ethanol, thus making its consumption redundant.
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PMID:Mechanism of action for reduction of ethanol intake in rats by the tachykinin NK-3 receptor agonist aminosenktide. 980 42

Capsaicin exerts its gastroprotective effect by stimulating primary afferent neurons, releasing calcitonin gene-related peptide (CGRP), which in turn increases gastric blood flow. In this work, the effects of capsaicin, rat alpha-CGRP, and relative peptides hCGRP(8-37) and beta-hCGRP, and substance P on cultured gastric mucosal cells independent of neural and vascular mechanisms were studied. Damage was produced by indomethacin, ethanol or taurocholate 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and trypan blue exclusion tests were used to assess viability of the cultured cells. Capsaicin administration alone did not injure gastric cells. However, capsaicin pretreatment potentiated the damaging effect of indomethacin and ethanol. In the sodium taurocholate model, capsaicin slightly protected the cells against injury. Alpha-rCGRP was protective against indomethacin, ethanol and taurocholate in a dose-dependent manner. hCGRP(8-37) and beta-hCGRP both dose-dependently prevented injury caused by indomethacin at concentrations about eight times higher than that of alpha-rCGRP, but substance P was ineffective in the three different damage models. A combination of alpha-CGRP and hCGRP(8-37) was also protective against indomethacin damage to a similar extent as use of either agent alone. The defence mechanism of capsaicin against gastric cell injury may in part be mediated by a direct effect of CGRP on gastric mucosal cells, in addition to effects dependent on neural and vascular mechanisms. hCGRP(8-37) has no antagonist effect against CGRP in this model, suggesting that CGRP receptors in this model may be different from those in other tissues.
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PMID:Calcitonin gene-related peptide protects cultured rat gastric mucosal cells. 985 48


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