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)

Intrathecal injection of 5-hydroxytryptamine (5-HT) or of substance P in mice elicited a behavioural syndrome consisting of reciprocal hindlimb scratching and biting or licking, directed towards the caudal parts of the body. 5-Hydroxtryptamine elicited more scratching than did substance P, which in turn caused a greater number of biting or licking responses. The 5-HT-induced responses were mimicked by 5,6-dihydroxytryptamine and inhibited by the 5-HT receptor blocker metergoline. The present findings indicate that 5-HT, injected intrathecally, may have similar effects as substance P in stimulating sensory pathways in the spinal cord.
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PMID:Similar behavioural effects of 5-hydroxytryptamine and substance P injected intrathecally in mice. 619 Jan 2

The antinociceptive effects of intrathecally administered 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent 5-HT receptor agonist, were studied in three behavioral tests in mice: the tail-flick test and the intrathecal substance P and N-methyl-D-aspartic acid (NMDA) assays. Intrathecal administration of 5-MeO-DMT (4.6-92 nmol/mouse) produced a significant prolongation of the tail-flick latency. This action was blocked by 5-HT3 and gamma-aminobutyric acidA (GABAA) receptor antagonists but not by 5-HT2, 5-HT1A, 5-HT1B or 5-HT1S receptor antagonists. Binding studies indicated that 5-MeO-DMT had very low affinity for 5-HT3 receptors. 5-MeO-DMT inhibited biting behavior while increasing scratching behavior induced by intrathecally administered substance P. The inhibition of biting behavior was antagonized by intrathecal co-administration of 5-HT1B and GABAA receptor antagonists while 5-HT1A, 5-HT1S, 5-HT2 and 5-HT3 receptor antagonists had no effect. 5-MeO-DMT-enhanced scratching behavior was inhibited by all the antagonists used except ketanserin and bicuculline, suggesting the involvement of 5-HT1A, 5-HT1B, 5-HT1S, 5-HT3 and GABAA receptors. NMDA-induced biting behavior was inhibited by 5-MeO-DMT pretreatment; this action was antagonized by 5-HT1B, 5-HT3 and GABAA receptor antagonists. The involvement of these receptors in 5-MeO-DMT action suggests that it may promote release of 5-HT (5-hydroxytryptamine, serotonin).
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PMID:Intrathecal 5-methoxy-N,N-dimethyltryptamine in mice modulates 5-HT1 and 5-HT3 receptors. 750 56

1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM. 5. Selective 5-HT receptor agonists were also tested on excitatory NANC responses. 5-Carboxamidotryptamine (5-CT, 0.1-100 MicroM) was the most potent, producing a concentration-dependent inhibition with an EC50 of 0.13 MicroM. Calculation of approximate IC25 values (concentration of the agonist required to give a 25% inhibition of the excitatory NANC response) gave a rank order of potency 5-CT > 5-HT> > 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) >alpha-methyl-5-hydroxytryptamine (alpha-Me-5HT). Sumatriptan, 5-methoxytryptamine (5-MeOT) and 2-methyl-5-hydroxytryptamine (2-Me-5HT) were essentially inactive with IC25> 100 MicroM.6. 5-HT (10 microM) did not significantly affect contractile responses to exogenously applied substance P(1 nM-10 Microm).7. The effect of 5-HT was unchanged after incubation with the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 100 Microm). However, pretreatment with charybdotoxin (ChTX,0.1-30 nM), a blocker of the large conductance Ca2+-activated K+channel (K+ca), produced a concentration-dependent inhibition of the effect of 5-HT (10 MicroM).8. 5-HT evokes a concentration-dependent inhibition of e-NANC bronchoconstriction in guinea-pig isolated bronchi but does not affect cumulative concentration-dependent contractile responses to substance P, suggesting that inhibition is via a prejunctional receptor. Effects of selective antagonists and agonists suggest that an atypical 5-HT receptor mediates this inhibition. The inhibitory effect of 5-HT does not involve the production of NO, but may involve the opening a ChTX-sensitive K+ca channel.These data suggest that an atypical 5-HT receptor inhibits the release of neuropeptides from sensory C fibres and may act as other inhibitory neuromodulators via the opening of a common K'channel.
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PMID:Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor. 751 94

This review shows that the role of 5-hydroxytryptamine (5-HT) in the regulation of nociception depends on the 5-HT receptor subtypes involved and on long-term functional changes in the 5-HT receptors. Stimulation of the 5-HT1 receptors, as well as of the 5-HT2 and 5-HT3 receptors, may reduce nociceptive sensitivity. In addition, activation of 5-HT2 and 5-HT3 receptors may also enhance nociceptive sensitivity. Up- or down-regulation of the 5-HT receptors may result in long-lasting changes, plasticity, in the 5-HT systems. Lesioning of 5-HT neurons induces denervation supersensitivity to 5-HT, and prolonged stimulation of 5-HT receptors may produce subsensitivity to 5-HT. In the spinal cord denervation supersensitivity to 5-HT may depend on reduced release of substance P (SP). An increase in the release of SP, on the other hand, may reduce the effects of 5-HT receptor activation. Long-term treatment with antidepressants which are used in clinical pain therapy appears to up-regulate the 5-HT1 receptors and to down-regulate the 5-HT2 receptors.
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PMID:The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity. 768 23

The aim of this study was to characterize, in conscious rats, the spinal cord 5-hydroxytryptamine (5-HT) receptors involved in mean arterial pressure (MAP) and heart rate (HR) regulation as well as to examine the influence of bulbospinal 5-HT fibers on cardiovascular responses to intrathecal (i.t.) substance P (SP). The i.t. injection of 5-HT or 5-carboxamidotryptamine (5-CT) (5-HT1A,1B,1D agonist) reduced MAP and increased HR in a dose-dependent manner. In contrast, the agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 5-HT1A agonist) and alpha-CH3-5-HT (5-HT1C and 5-HT2) only caused a decrease in HR, while the agonist 2-CH3-5-HT (5-HT3) was devoid of cardiovascular effects. The vasodepressor response to 5-CT was antagonized by methiothepin but not affected by mesulergine, ketanserin, propranolol, or yohimbine. However, all five antagonists reduced the HR increase to 5-CT. Ketanserin, propranolol, mesulergine, yohimbine, and methylsergide were without effect on resting MAP, while methiothepin reduced MAP. Methiothepin, ketanserin, and methylsergide increased resting HR, yet the other antagonists had no effect on this parameter. Rats treated with p-chlorophenylalanine or 5,7-dihydroxytryptamine, but not with 6-hydroxydopamine, exhibited higher resting HR than that of control rats. Although the resting MAP was unaffected, the pressor response to i.t. SP was significantly enhanced by either 5-HT toxin. The results suggest that the receptor mediating the depressor response to 5-HT and 5-CT conforms with the broad pharmacological profile of a 5-HT1-like receptor and is unlikely to be of the 5-HT2 or 5-HT3 subtype. Since the HR response evoked by 5-CT was blocked by antagonists that exhibit affinities for various 5-HT receptor subtypes, it is suggested that a nonspecific blockade or, alternatively, that more than one receptor contributes to this cardiac effect. In addition, the results raise the possibility that a spinal 5-HT input, likely mediated by 5-HT2 receptors, tonically inhibits HR. Hence, an antagonistic interaction between 5-HT and SP is proposed to play a role in the control of arterial blood pressure in the spinal cord.
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PMID:Spinal cord serotonin receptors in cardiovascular regulation and potentiation of the pressor response to intrathecal substance P after serotonin depletion. 769 81

1. Cyclophosphamide (CYP) (150 mg kg-1, i.p. 0.5-48 h before) caused a time-dependent plasma protein extravasation in the rat urinary bladder with the maximal extravasation occurring at between 2 and 4 h after administration of the drug. 2. Prior capsaicin desensitization of capsaicin-sensitive primary afferent neurones (CSPANs) (50 mg kg-1, s.c., 4 days before) resulted in approximately 50% inhibition of the magnitude of the extravasation response at the 2 h time-point. 3. Intraperitoneal (i.p.) pretreatment with the tachykinin NK1 receptor antagonist, RP 67,580 (0.44 mg kg-1) or the bradykinin B2 receptor antagonist, Hoe 140 (0.13 mg kg-1) had significant inhibitory effects, giving responses of 56 +/- 6% and 39 +/- 4% of the control extravasation response to CYP treatment after 2 h. Pretreatment with the tachykinin NK2 receptor antagonist, SR 48,968 (0.3 mg kg-1, i.p.), the histamine H1 receptor blocker, chlorpheniramine (10 mg kg-1, i.p.), the 5-HT receptor blocker, methysergide (6 mg kg-1, i.p.) or the cyclo-oxygenase inhibitor indomethacin (5 mg kg-1, i.p.) had no significant effect upon the development of the extravasation response at this same time-point. 4. In rat isolated urinary bladder strips, the active metabolite of CYP, acrolein (1-300 microM) produced a concentration-dependent contraction that was significantly reduced by in vitro capsaicin desensitization (10 microM for 15 min) indicating direct stimulation of CSPANs. CYP was without appreciable effect. 5. The effect of acrolein in vitro was significantly reduced by pretreatment of the bladder with a combination of tachykinin NK1 and NK2 receptor antagonists, RP 67,580 (3 microM) and SR 48,968 (1 microM). The dose-response curve to acrolein was also significantly inhibited by treatment with indomethacin (10 microM) and slightly affected by Hoe 140 (1 microM). 6. These findings demonstrate the contribution of CSPANs to the development of CYP-induced cystitis.Plasma protein extravasation involves activation of tachykinin NKI and bradykinin B2 receptors.Activation of CSPANs in the urinary bladder is likely to be due to the conversion of CYP into its active metabolite, acrolein, and not to a direct effect of CYP upon these nerve-endings.
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PMID:Characterization of the capsaicin-sensitive component of cyclophosphamide-induced inflammation in the rat urinary bladder. 803 84

The effects of anti-idiotypic antibodies (alpha-id) that recognize serotonin [5-hydroxytryptamine (5-HT)] receptors on myenteric neurons of the guinea pig small intestine were characterized electrophysiologically, and alpha-id binding sites were located immunocytochemically. Initial applications of the alpha-id mimicked each of three actions of 5-HT: a rapid depolarization, associated with a fall in input resistance (Rin), which was inhibited by the 5-HT3 antagonists tropisetron (> or = 1 microM) and renzapride (100 microM); a slow membrane depolarization, associated with increased Rin, that was inhibited by the 5-HT1P antagonist renzapride but was unaffected by a 5-HT4 blocking concentration of tropisetron (10 microM); and a hyperpolarization, associated with decreased Rin, that was antagonized by the 5-HT1A inhibitor NAN-190. Cross-desensitization was observed between responses to 5-HT and the alpha-id. After exposure to the alpha-id, subsequent responses to the alpha-id, 5-HT, and stimulus-evoked slow excitatory postsynaptic potentials were antagonized; however, responses to carbachol and substance P were unaffected. The alpha-id thus specifically inhibits the effects of endogenously released and exogenously applied 5-HT. The alpha-id bound to sites on myenteric and submucosal neurons and a subepithelial nerve plexus. Binding of the alpha-id was blocked by 5-HT1P-, 5-HT3-, and 5-HT4-specific antagonists. We concluded that the alpha-id binds selectively to all known subtypes of 5-HT receptor in the enteric nervous system and is thus useful for investigating the gastrointestinal function of 5-HT.
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PMID:Analysis of the role of 5-HT in the enteric nervous system using anti-idiotopic antibodies to 5-HT receptors. 816 80

5-Hydroxytryptamine (5-HT) specifically and reversibly inhibits nicotine-induced currents and catecholamine release in bovine adrenal chromaffin cells in culture. Pharmacological analysis indicates that the inhibition is not mediated by known 5-HT receptor subtypes. The inhibition is noncompetitive over a range of nicotine concentrations between 1 and 100 microM. Preincubation with either 5-HT or substance P significantly protects the response from nicotine-induced desensitization. It is concluded that 5-HT inhibits nicotinic acetylcholine receptors on bovine adrenal chromaffin cells, probably by binding to a noncompetitive site on the receptor itself. Because both blood and the chromaffin cells contain 5-HT, the inhibition provides an opportunity for negative control of catecholamine secretion from the adrenals.
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PMID:Serotonin modulates nicotinic responses of adrenal chromaffin cells. 851 80

The 5-HT receptor mediating postjunctional relaxation of precontracted guinea-pig ileum has been characterized using several agonists and antagonists. Substance P precontracted tissues were potently relaxed by 5-HT (5-hydroxytryptamine, serotonin), 5-CT (5-carboxamidotryptamine) and several other indoles. The rank order of potency, with pEC50 values in parentheses, was 5-CT (7.6) > 5-methoxytryptamine (5.7) > 5-HT (5.5) > alpha-methyl-5-HT (4.7) > 2-methyl-5-HT (< 4.0) = tryptamine (< 4.0) = N,N-dimethyl-tryptamine (< 4.0) = N,N-dimethyl-5-HT (< 4.0) = dipropyl-5-CT (< 4.0) = sumatriptan (< 4.0). 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin) acted as a potent (6.3), but partial, agonist with respect to 5-HT. The responses to 5-CT were antagonized by several compounds with the following rank order of affinity, with pKB values in parentheses: LSD (lysergic acid diethylamide; 8.1) = mesulergine (7.8) > methysergide (7.6) = spiperone (7.6) > clozapine (7.3) >> (-)-pindolol (< 6.0) > ketanserin (< 6.0) = ondansetron (< 6.0) = GR 113808 ([1-(2-methane-sulphonamido-ethyl)-piperidin-4-yl]-methyl-in dole-3- carboxylate maleate; < 6.0). The relaxant responses to 5-HT were also resistant to tetrodotoxin. These data are consistent with a functional 5-HT receptor, mediating relaxation of guinea-pig ileum, which exhibits an operational profile similar to that of the cloned guinea-pig 5-ht7 receptor. This study, therefore, provides evidence for a functional correlate of the 5-ht7 gene product.
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PMID:Characterization of a postjunctional 5-HT receptor mediating relaxation of guinea-pig isolated ileum. 856 92

Perfusion of 6-hydroxydopamine into the rat knee and trachea induces plasma extravasation, possibly by tissue-specific mechanisms involving sympathetic and sensory nerves respectively, and we aimed to identify the mediators which contribute to this response in skin. 6-Hydroxydopamine (both hydrobromide and hydrochloride salts), dose dependently increased plasma extravasation into rat dorsal skin, however, when compared to bradykinin or the tachykinin NK1 receptor agonist GR73632, high concentrations of 6-hydroxydopamine (1-10 mumol/site) were required. The response to 6-hydroxydopamine was not inhibited in chemically sympathectomised rats (6-hydroxydopamine, 300 mg/kg i.p. over 7 days) but was significantly reduced by co-administration with the histamine (H1) and the 5-HT receptor antagonists mepyramine and methysergide and in skin sites pre-injected with compound 48/80 (4 micrograms, -18 h) to degranulate dermal mast cells. The response was not inhibited by co-injection of the tachykinin NK1 receptor antagonist SRI40333 or by the cyclo-oxygenase inhibitor indomethacin (5 mg kg-1 i.p., -30 min) except at the lowest dose of 6-hydroxydopamine (1 mumol/site). We conclude that 6-hydroxydopamine is not a potent or selective mediator of increased vascular permeability in rat skin but, at high concentrations, may induce oedema formation via release of vasoactive amines from mast cells, augmented by generation of prostaglandins.
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PMID:Investigation of 6-hydroxydopamine-induced plasma extravasation in rat skin. 877 59


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