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)

Biochemical, histochemical and neurophysiological data suggest that substance P and somatostatin are neurotransmitters for primary afferent neurons. This study used intrathecal administration of these peptides and others (neurotensin and vasoactive intestinal polypeptide) in chronically catheterized, environmentally adapted, freely moving rats to evaluate their effects on unconditioned behavior. Substance P and somatostatin each elicited behaviors which were dose related. The behaviors included caudally directed biting and licking along with hindlimb scratching, writhing and retching. The behavioral responses were rapid in onset (1 min) and, in the case of substance P, short in duration (3 min). Vehicle, neurotensin and vasoactive intestinal polypeptide were without effect. These results demonstrate the ability of substance P and somatostatin to induce behavior in rats upon intrathecal administration and extend previous studies in mice.
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PMID:Intrathecal substance P and somatostatin in rats: behaviors indicative of sensation. 617 76

1. The selective NK1 receptor antagonist, CP-99,994, produced dose-related (0.1-1.0 mg kg-1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2. Parallel studies with the enantiomer, CP-100,263 (1 mg kg-1, s.c.), which is > 1,000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuSO4, loperamide, cisplatin and apomorphine-induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately 1/10th the potency of CP-99,994. 3. The 5-HT3 receptor antagonist, tropisetron (1 mg kg-1, s.c.) inhibited retching and vomiting to cisplatin and ipecac, but not CuSO4 or loperamide. 4. CP-99,994 (1 mg kg-1, i.v.) blocked retching induced by electrical stimulation of the ventral abdominal vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves. CP-99,994 (1 mg kg-1, i.v.) did not alter baseline cardiovascular and respiratory parameters and it failed to block the characteristic heart rate, blood pressure and respiratory rate/depth changes in response to i.v. 2-methyl-5-HT challenge (von Bezold-Jarisch reflex). 5. Using in vitro autoradiography, [3H]-substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus solitarius being much greater than in the area postrema. This binding was displaced by CP-99,994 in a concentration-related manner. 6. In dogs, CP-99,994 (40 micrograms kg-1 bolus and 300 micrograms kg-1 h-1, i.v.) produced statistically significant reductions in vomiting to CuSO4 and apomorphine as well as retching to CuSO4. 7. Together, these studies support the hypothesis that the NK1 receptor antagonist properties of CP-99,994 are responsible for its broad spectrum anti-emetic effects. They also suggest that CP-99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.
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PMID:The anti-emetic effects of CP-99,994 in the ferret and the dog: role of the NK1 receptor. 754 98

The tachykinin NK1 receptor antagonist CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine) (0.3-3 mg/kg i.v.), but not its inactive enantiomer CP-100,263, attenuated the retching and vomiting induced by cisplatin (10 mg/kg i.v.) in the ferret. CP-99,994, 3 mg/kg i.v., prevented vomiting in all ferrets tested. Since substance P is the preferred ligand at the NK1 receptor subtype these data support a role for the release of this peptide during the emetic response induced by cytotoxic chemotherapeutic agents.
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PMID:The tachykinin NK1 receptor antagonist CP-99,994 attenuates cisplatin induced emesis in the ferret. 811 5

The ferrets' responsiveness to several known and putative emetic agents was evaluated using a variety of agents that were injected subcutaneously and/or intravenously. Apomorphine was consistently emetic at relatively high doses (100 micrograms/kg) when injected subcutaneously in large male ferrets (> or = 1.4 kg). The responsiveness to apomorphine was anomalous in that subcutaneous injections produced a more consistent response than intravenous ones. In addition, ferrets rapidly become tolerant or tachyphylactic to subcutaneously administered apomorphine. Area postrema ablation, but not abdominal vagotomy, rendered ferrets refractory to the emetic effects of apomorphine. This species, relative to dog and humans, proved to be insensitive to a variety of pharmacologic agents including angiotensin II, gastrin, histamine, Leu-enkephalin, neurotensin, serotonin, and vasopressin. Cisplatin elicited forceful retching and emesis. Emetic responses were obtained with substance P and Met-enkephalin in individual animals but were inconsistent. Sensitivity to DAGO [D-Ala2,MePhe4,Gly-ol5 enkephalin] was variable. Results of this study indicate that the ferret is not an optimal model for all forms of emesis.
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PMID:Behavioral studies of emetic sensitivity in the ferret. 849 72

The potent, selective, tachykinin NK1 receptor antagonist, CP-122,721 ([(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2- phenylpiperidine]), at 0.01-1 mg/kg, s.c. reduced retching and vomiting elicited by loperamide, copper sulfate, ipecac syrup and cisplatin in a dose-dependent manner. ID50 values after subcutaneous administration ranged from 0.02 mg/kg (loperamide) to 0.08 mg/kg (ipecac). Oral CP-122,721 reduced cisplatin-induced emesis with an ID50 of approximately 0.08 mg/kg. The less active (2R, 3R)-enantiomer, CP-132.687, did not significantly suppress retching or vomiting induced by any of the emetogens. These data support the hypothesis that CP-122,721 blocks emesis by a specific action at tachykinin NK1 receptors. Its broad spectrum of antiemetic activity suggests a central site of action.
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PMID:Broad spectrum antiemetic effects of CP-122,721, a tachykinin NK1 receptor antagonist, in ferrets. 881 51

This paper is the first to describe aspects of the mechanics of retching in the insectivore Suncus murinus (house musk shrew) and in an animal of such a small size (approximately 50 g). In anaesthetised animals using the novel stimulus of mechanical stimulation of the upper gastrointestinal tract as the provocative stimulus the frequency of retching was found to be about 4 retches/s, a much higher frequency than in other species (dog, cat, ferret). These studies show that quantification of retching in Suncus cannot be undertaken using direct observation. The temporal pattern of the emetic response was characterised in conscious Suncus using motion (1 Hz, 5 min) and nicotine (20 mg/kg s.c.). The ultrapotent capsaicin analogue resiniferatoxin (100 micrograms/kg s.c.) was discovered to be highly emetic and comparative studies showed that nicotine and resiniferatoxin induced the most intense responses with episodes (retches and a vomit) occurring every 10-15 s. The retching response to mechanical stimulation in the anaesthetised Suncus was not blocked by a 5-HT3 receptor antagonist (granisetron, 1-5 mg/kg s.c.), a tachykinin NK1 receptor antagonist (CP-99,994 20 mg/kg s.c. dihydrochloride salt (9+) -(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine) or morphine (2 mg/kg s.c.) but was blocked by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT 100 micrograms/kg s.c.). Suncus appears to be a suitable animal in which to study the pharmacology of the emetic response to mechanical stimulation of the gut. The results are discussed in the light of studies of the pharmacology of emesis in other species.
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PMID:The pharmacology of the emetic response to upper gastrointestinal tract stimulation in Suncus murinus. 883 19

1. The anti-emetic effects of the NK1 tachykinin receptor antagonist, CP 99,994 (10 mg kg-1) were investigated in the ferret using a cisplatin-induced acute (day 1) and delayed (day 2 and 3) retching and vomiting model. 2. With a single cisplatin (10 mg kg-1) emetogenic challenge, the i.p. administration of CP 99,994 given as a single injection immediately following the first emetic episode, promptly abolished the retching and vomiting for a 4 h period. CP 99,994 was as efficacious as ondansetron (1.0 mg kg-1). The general toxicity of cisplatin 10 mg kg-1 precluded its use in studies of delayed emesis. 3. With a single cisplatin (5 mg kg-1) emetogenic challenge, the single administration of either CP 99,994 (10 mg kg-1) or ondansetron (1.0 mg kg-1) immediately following the first emetic episode markedly reduced or abolished the retching and vomiting for 4 h. Such single treatments failed to modify significantly the intensity of delayed emesis appearing on the second and third day. 4. With a cisplatin (5 mg kg-1) emetogenic challenge, administration of CP 99,994 (10 mg kg-1) at 8 hourly intervals, the first injection being administered 30 s post cisplatin, was associated with 4 or more abolitions of emesis during both the acute and delayed phase. A 4 hourly administration of CP 99,994 for 20 h during delayed emesis completely abolished the retching and vomiting. 5. It is concluded that cisplatin 5 mg kg-1 provides an emetogenic challenge causing an acute and delayed phase of retching and vomiting and that CP 99,994 can abolish both phases. The results may be relevant to the understanding and treatment of chemotherapy-induced emesis in man.
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PMID:The action of the NK1 tachykinin receptor antagonist, CP 99,994, in antagonizing the acute and delayed emesis induced by cisplatin in the ferret. 892 42

The activity of a selective tachykinin NK1 receptor antagonist, PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph), was examined in radioligand binding studies, in a [Sar9,Met(O2)11]substance P-induced foot-tapping model in the gerbil, and in cisplatin-induced acute and delayed emesis in the ferret. In radioligand binding studies, PD 154075 showed nanomolar affinity for the human, guinea-pig, gerbil, dog and ferret NK1 receptors with an approximate 300 times lower affinity for the rodent NK1 receptor. Using NK2,NK3 receptors and a range of other receptor ligands, PD 154075 was shown to exhibit a high degree of selectivity and specificity for the human type NK1 receptor. Following subcutaneous administration PD 154075 dose dependently (1-100 mg/kg) antagonised the centrally mediated [Sar9,Met(O2)11] substance P-induced foot tapping in the gerbil with a minimum effective dose (MED) of 10 mg/kg. The ability of PD 154075 to readily penetrate into the brain following oral administration was confirmed by its extraction and high performance liquid chromatography assay from the rat brain. PD 154075 was shown to achieve a relatively fast and sustained brain concentration (brain/plasma ratios ranged from 0.27 to 0.41 during the time period of 0.25-12 h). Further pharmacokinetic studies revealed that the absolute oral bioavailability of PD 154075 in the rat was (mean +/- S.D.) 49 +/- 15%. PD 154075 (1-30 mg/kg, i.p.) dose dependently antagonised the acute vomiting and retching in the ferret measured for 4 h following administration of cisplatin (10 mg/kg, i.p.) with a MED of 3 mg/kg. The administration of a lower dose of cisplatin (5 mg/kg, i.p.) in the ferret induces both an acute (day 1) and delayed (days 2 and 3) phase of emesis. The i.p. administration of PD 154075, 10 mg/kg three times a day for 3 days, almost completely blocked both the acute and delayed emetic responses. In the same study, the 5-HT3 receptor antagonist ondansetron (1 mg/kg, i.p., t.i.d.) was also very effective against the acute emetic response observed during the first 4 h following cisplatin, but it was only weakly active against the delayed response. In conclusion, PD 154075 is a selective and specific high affinity NK1 receptor antagonist with good oral bioavailability which is effective against both acute and delayed emesis induced by cisplatin in the ferret.
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PMID:The tachykinin NK1 receptor antagonist PD 154075 blocks cisplatin-induced delayed emesis in the ferret. 906 90

1. The NK1 receptor antagonist CP-99994 has been shown to prevent vomiting elicited by both peripherally and centrally acting emetogens in ferrets and dogs. These results have now been extended to another stimulus, provocative motion, and another species, the cat. 2. CP-99994 displaced [3H]-substance P from cat cortex with IC50 of 0.52 +/- 0.08 nM. Following s.c. administration, peak plasma drug levels were achieved at 30 min. The plasma drug half life was 1.4 h. 3. Subcutaneous administration of CP-99994 inhibited motion-induced vomiting in the cat with an ED50 of 144 micrograms kg-1 but did not change the epiphenomena associated with provocative motion in the cat over the dose range of 30 to 300 micrograms kg-1. The antiemetic effect of CP-99994 can be attributed to antagonism of the NK1 receptor because its enantiomer, CP-100,263, which is 900 fold weaker as an NK1 antagonist, had no effects on any response to provocative motion. 4. The inhibitory effect of CP-99994 on motion-induced retching and vomiting is consistent with a central site of antiemetic action, potentially at the level of the motor nuclei responsible for these behaviours. 5. An investigation into whether the failure of CP-99994 to alter the epiphenomena will also predict a lack of anti-nausea effects in man will provide critical information on the neural organization of the emetic reflex.
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PMID:The effect of CP-99994 on the responses to provocative motion in the cat. 911 85

The ability of tachykinin NK1 receptor antagonists to inhibit GR73632 (D-Ala-[L-Pro9,Me-Leu8]substance P-(7-11))-induced foot tapping in gerbils was employed as an indirect measure of brain penetration and this was compared with their ability to prevent acute emesis induced by cisplatin in ferrets. (+)-GR203040 ((2S,3S and 2R,3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin- 3-yl)-amine), CP-99,994 ((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl piperidine) dihydrochloride), and L-742,694 (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(5-(3-oxo-1,2, 4-triazolo)methylmorpholine) potently inhibited GR73632-induced foot tapping (ID50 < or = 0.85 mg/kg), and acute retching induced by cisplatin (ID50 < or = 0.18 mg/kg). RPR100893 ((3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-m ethoxyphenyl)proprionyl] perhydroisoindol-4-ol) was not a potent antagonist of retching (ID50 4.1 mg/kg) or foot tapping (ID50 > 10 mg/kg). High doses (3-10 mg/kg) of CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl] -4-piperineamine) dihydrochloride), FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(pi peridinyl)piperidin-1-yl)acetyl)amino]propane) were required to inhibit foot tapping; these agents were not anti-emetic in this dose range. SR140333 ((S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane; 3-10 mg/kg) failed to inhibit foot tapping or emesis. Affinities for the human and ferret tachykinin NK1 receptor were highly correlated (r = 0.93, P = 0.0008). Inhibition of foot tapping in gerbils, but not NK1 receptor binding affinity, predicted anti-emetic activity in ferrets (r = 0.75, P < 0.01). These findings confirm that the anti-emetic activity of tachykinin NK1 receptor antagonists is dependent on brain penetration.
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PMID:In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists. 919 73


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