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)

An enteric neural receptor for serotonin (5-HT) has been characterized. This receptor was assayed, using 3H-5-HT as a radioligand, by rapid filtration of isolated enteric membranes and by radioautography. In addition, intracellular recordings were made from ganglion cells of the myenteric plexus. High affinity, saturable, reversible, and specific binding of 3H-5-HT was demonstrated both to membranes of the dissected longitudinal muscle with adherent myenteric plexus and the mucosa-submucosa. Radioautographs showed these 3H-5-HT binding sites to be in myenteric ganglia and in a broad unresolved band at the mucosal-submucosal interface. Antagonists active at receptors for other neurotransmitters than 5-HT, at either of the two known types of CNS 5-HT receptor, and at 5-HT uptake sites on serotonergic neurons failed to inhibit binding of 3H-5-HT. The structural requirements of analogues for binding to the enteric 5-HT receptor matched the known pharmacology of M or neural 5-HT receptors. A novel 5-HT antagonist was found. This compound, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP), antagonized the action of 5-HT on type II/AH cells of the myenteric plexus but did not affect the release or actions of acetylcholine (nicotinic or muscarinic) or substance P. 5-HTP-DP was also an equally potent displacer of 3H-5-HT from its binding sites on enteric membranes. It is concluded that the sites responsible for specific binding of 3H-5-HT are enteric M or neural 5-HT receptors. These receptors differ from those now known to be present in the CNS.
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PMID:The enteric neural receptor for 5-hydroxytryptamine. 387 89

Research on the role of serotonin (5-hydroxytryptamine, 5-HT) in the function of the enteric nervous system has been impeded by the lack of specific inhibitors of the enteric neural actions of 5-HT. Saturable, reversible, high affinity enteric binding sites for 3H-5-HT have recently been characterized and radioautographically located. Affinity for the 3H-5-HT binding site requires an indole ring substituted with a free hydroxyl group. These 3H-5-HT binding sites have been proposed to be enteric neural 5-HT receptors. This hypothesis was tested in the current study by comparing the ability of compounds to inhibit the binding of 3H-5-HT with their electrophysiologically determined actions on myenteric neurons. 5-Methoxytryptamine did not inhibit the binding of 3H-5-HT to enteric membranes and neither mimicked nor antagonized the effects of 5-HT on the membrane potential of myenteric neurons. Two dipeptides of 5-hydroxytryptophan, N-acetyl- and N-hexanoyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP and N-hex-5-HTP-DP) inhibited the binding of 3H-5-HT (K1 = 0.25 microM for 5-HTP-DP and 1.19 microM for N-hex-5-HTP-DP). 5-HTP-DP applied by pressure microejection or superfusion (10 microM) antagonized the slow postsynaptic depolarization of myenteric neurons evoked by microejection of 5-HT. 5-HTP-DP also blocked the 5-HT-induced presynaptic reduction in amplitude of nicotinic fast synaptic potentials; however, 5-HTP-DP itself did not affect these responses. Moreover, 5-HTP-DP also failed to affect responses of myenteric neurons to microejected substance P, their muscarinic response to acetylcholine, or antidromic action potentials. In contrast, both dipeptides blocked the slow synaptic potentials seen in type II/AH neurons following stimulation of fiber tracts in interganglionic connectives. These data support the hypotheses that enteric 3H-5-HT binding sites are enteric neural 5-HT receptors, that dipeptides of 5-hydroxytryptophan are specific antagonists at these receptors, and that 5-HT is one of the mediators of slow synaptic potentials in the myenteric plexus.
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PMID:Specific antagonism of enteric neural serotonin receptors by dipeptides of 5-hydroxytryptophan: evidence that serotonin is a mediator of slow synaptic excitation in the myenteric plexus. 387 33

Some neurotransmitter-receptor interactions have been studied in an attempt to determine how L-prolyl-L-leucyl-glycinamide (MIF-I) exerts its antiparkinson effect. MIF-I affected neither the contractile responses of isolated mouse vas deferens and guinea pig ileum to noradrenaline, acetylcholine, substance P and histamine, nor the inhibitory effects of dopamine and GABA on the rat vas deferens and guinea pig ileum. MIF-I, as well as L-leucine and Pro-Leu, antagonized the contractile response of the ileum to 5-hydroxytryptamine (5-HT). Behavioural tests were used to examine the action of MIF-I on CNS transmitter-receptor interactions. MIF-I did not modify the circling produced by either dopamine agonists in nigro-striatal lesioned rats of 5-HT agonists in rats with a lesion of the medial raphe nucleus. MIF-I affected neither 5-hydroxytryptophan-induced head twitches in mice, which is a measure of 5-HT receptor stimulation, nor striatally-evoked head turning in the rat, which is a model for brain GABA function. It is concluded that MIF-I, at the doses used, does not directly modify the function of any of the CNS transmitter examined. Other possibilities to explain its antiparkinson action are discussed.
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PMID:Effect of L-prolyl-L-leucyl-glycinamide (MIF-I) on some neutrotransmitter-receptor interactions. 617 54

Since substance P (SP) has been demonstrated to coexist with serotonin (5-HT) in the same population of neurons in the descending raphe system, we have studied the possibility of interactions between these neurotransmitters in other brain areas. Brain nuclei were punched from frozen 300-micron slices of rat brain and extracted with 0.1 M HCIO4 or 2 M acetic acid prior to assay, respectively, of 5-HT content by HPLC with electrochemical detection or SP content by specific radioimmunoassay. Ten days after injection of rats with the 5-HT neurotoxin P-chloroamphetamine (PCA, 10 mg/kg, B.W., i.p.) or 3 days after 5-HT synthesis blockade with p-chlorophenylalanine (PCPA, 300 mg/kg, B.W., i.p.), the 5-HT content of all brain nuclei studied was reduced by means of, respectively, 50% and 81%. In PCA-treated animals, the SP content of the periaqueductal grey matter was significantly increased; PCPA treatment caused, in addition, large increases in the SP content of five other brain nuclei. Blockade of 5-HT receptors by methysergide (15 mg/kg for 5 days) did not significantly change 5-HT levels or turnover, but resulted in 50-200% increases in the SP content of 10 of the 28 brain nuclei studied. Significant decreases in the SP content of numerous areas were seen following treatments (pargyline 30 mg/kg, alone or in combination with 5-hydroxytryptophan, 60 mg/kg) that simultaneously increased 5-HT levels. These results illustrate the modulation of distinct SP-containing systems of the rat brain by perturbation of central serotoninergic pathways and indicate a reciprocal relationship between the SP and 5-HT concentrations of numerous brain nuclei, in particular n. striae terminalis, n. raphe dorsalis, n. accumbens, n. septi, substantia grisea centralis, and n. raphes medianus.
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PMID:Perturbation of rat brain serotonergic systems results in an inverse relation between substance P and serotonin concentrations measured in discrete nuclei. 619 16

Intracerebroventricularly administered Arg-Pro-Lys-Pro-Gln-Gln-Phe-Gly-Leu-Met-NH2 (substance P, SP) enhanced the accumulation of DOPA after inhibition of the aromatic L-amino acid decarboxylase in the rat brain. SP also stimulated locomotor activity in a dose-dependent manner. A total of 31 structural analogues of SP were evaluated with respect to the action on brain monoamine synthesis as well as on locomotor activity. Catecholamine synthesis: SP1-10 was inactive which indicated that the [Met11]-NH2 terminal is essential for biological activity; [Leu10], [Phe7] and [Gln6] were also essential for activity; the minimum length requirement for activity was a hexapeptide amide structure. D-Amino acids in positions 8 or 9 increased activity. [D-Pro2]p-SP and [pGlu5, Gly7]-SP5-11 were active in the dopamine-rich areas, but inactive in the noradrenaline (norepinephrine)-predominant parts of the brain. The inactive [Ile7]-SP potentiated the effect of SP. Neither SP nor its analogues, with the exception of [Lys5,D-Leu8,D-Phe9]-SP5-11, increased the synthesis of 5-hydroxytryptophan (5-HTP). Locomotor activity: SP1-10 and [D-Phe9]-SP were as active as SP; [Ile7]-SP and [Ile7, Ile8]-SP were inactive and they did not antagonize the effect of SP. The results indicate that after chemical manipulation of the SP molecule it is possible to obtain great variation in activity and to dissociate to some extent the behavioural effects from those on brain catecholamine synthesis.
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PMID:Substance P: structural requirements for the activation of brain catecholamine synthesis and locomotor activity in rats. 619 36

The effects of substance P (SP), angiotensin II, oxotremorine and prostaglandin D2 (PG D2) on thyrotropin-releasing hormone (TRH) and thyrotropin (TSH) secretion in rats were studied. Either SP (100 micrograms/kg), angiotensin II (500 micrograms/kg), oxotremorine (1.0 mg/kg) or PGD2 (500 micrograms/kg) was injected intravenously or intraperitoneally, and the rats were serially decapitated. TRH, TSH and thyroid hormone were measured by means of a specific radioimmunoassay for each. The hypothalamic immunoreactive TRH (ir-TRH) contents were significantly increased by oxotremorine or SP and significantly decreased by angiotensin II, but no by PG D2. The plasma ir-TRH concentrations were significantly increased by angiotensin II, but not by oxotremorine, SP or PG D2. The plasma TSH levels were significantly increased by angiotensin II and significantly decreased by oxotremorine, SP or PG D2 in a dose-related manner. The plasma ir-TRH and TSH responses to cold were inhibited by oxotremorine, SP or PG D2, but enhanced by angiotensin II. The plasma TSH response to TRH was inhibited by SP, but enhanced by angiotensin II. The plasma TSH response to TRH did not differ from that of the control after PG D2 injection. In the haloperidol- or para-chlorophenylalanine (PCPA)-pretreated group, the inhibitory effect of PG D2 or oxotremorine on TSH release was prevented, while in the L-DOPA- or 5-hydroxytryptophan (5-HTP)-pretreated group, the inhibitory effect of SP on TSH release was prevented.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of substance P, angiotensin II, oxotremorine and prostaglandin D2 on thyrotropin secretion in rats. 620 27

The selective NK3 tachykinin agonist senktide evokes in rodents 5-HT mediated behaviors, including 5-HT2 receptor-mediated wet dog shakes (WDS) and head shakes (HS). It was observed previously that genetically selected Sardinian alcohol-preferring (sP) rats show a small number of WDS and HS following intracerebroventricular (ICV) injection of senktide. The present study was aimed at confirming these observations and at providing information on the reasons accounting for the anomalous response of sP rats. Senktide (500-2000 ng/rat, ICV) produced a much lower number of WDS and HS in sP rats than in nonselected Wistar (nsW) rats. Both behaviors were suppressed by the 5-HT2 antagonist ritanserin (1 mg/kg, subcutaneously), confirming that 5-HT2 receptors mediate the response. HS induced by the ICV injection of 5-HT agonists endowed with marked activity at 5-HT2 receptors, such as quipazine (1500-6000 ng/rat) or DOI (500-3500 ng/rat), were much less pronounced in sP rats than in nsW rats. Moreover, WDS following peripheral injection of 5-hydroxytryptophan, 25-100 mg/kg, and carbidopa, 12.5 mg/kg, were less intense in sP and in ethanol-naive sP rats than in nsW and in Sardinian alcohol-nonpreferring rats. These findings suggest that sP rats have an inherent different regulation of central 5-HT2 mechanisms.
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PMID:Low responsiveness to agents evoking 5-HT2 receptor-mediated behaviors in Sardinian alcohol-preferring rats. 754 92

We investigated the influence of four substances on the excitability of lumbar motoneurons. These substances, three of which coexist in the same bulbospinal descending pathways that end, for the most part, around motoneurons (MNS), are: 5-hydroxytryptamine (5-HT), substance P (SP) and thyrotropin-releasing hormone (TRH). We also studied the effects of clonidine, an alpha 2 noradrenergic (NA) agonist. This study was carried out in rats spinalized at T5 and treated three weeks earlier with 5-7 dihydroxytryptamine (5-7 DHT). Under these conditions, the following responses were observed: 5-HTP (5-HT precursor) intraperitoneally (I.P.), 5-HT intrathecally (I.T.), TRH (I.P. or I.T.) and substance P (I.T.) all elicited strong excitation of MNS as measured by integrated EMG of the hindlimb muscles; substance P reduced by almost half the response to 5-HTP given one hour and 24 hours later; TRH given acutely did not modify the response to 5-HTP, but given chronically for 21 days markedly increased the response to this substance. Clonidine by itself decreased the excitability of MNS and antagonized the excitatory effects of 5-HTP and TRH. In two separate pilot trials, cyproheptadine, a 5-HTP antagonist, decreased the manifestations of spasticity in a patient with a partial spinal lesion. It would appear that clonidine may have potential use in the management of spasticity.
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PMID:Action of 5-hydroxytryptamine, substance P, thyrotropin releasing hormone and clonidine on spinal neuron excitability. 754 99

Brofaromine is a tight-binding, reversible inhibitor of monoamine oxidase-A (MAO-A), with concomitant serotonin (5-HT) uptake-inhibiting properties. In psychopharmacologic investigations, the compound shows the properties expected of an MAO inhibitor, antagonizing the effects of reserpine, tetrabenazine, and 5-hydroxytryptophan in rats and mice, and suppressing rapid eye movement sleep in cats. Brofaromine showed antidepressant-like activity in a rat social conflict test. In radioligand binding assays, brofaromine exhibited weak or no interaction with alpha 1- and alpha 2-noradrenergic, 5-HT1, 5-HT2, 5-HT3, cholinergic, histamine H1 and H2, mu-opiate, GABAA, benzodiazepine, adenosine, neurotensin, and substance P receptors. Comparison of in vitro and in vivo potencies to inhibit 5-HT uptake with those of reference drugs, and direct evidence in patients and volunteers suggest that 5-HT uptake inhibition plays a role in the clinical profile of brofaromine.
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PMID:Brofaromine: a monoamine oxidase-A and serotonin uptake inhibitor. 831 93

A large number of biologically active substances have been identified and characterised in the respiratory tract of several mammals. These substances (amines and peptides) exert important regulatory influences on respiratory functions, and they act as neurotransmitters/neuromodulators, both being released from nerve terminals as neuroendocrine cells. However, these substances can also have other effects which suggest a paracrine action. Thus, to understand the role of amines and peptides in the lung, it is important to explore their localisation in different species. By using immunocytochemical staining methods we have studied the morphology and distribution of serotonin-, Substance P-, neuropeptide Y- and VIP-like immunoreactivity in the adult mouse lung. Moreover a pretreatment with colchicine, pargyline and 5-hydroxytryptophan as staining enlargement method was made. A widespread distribution of isolated endocrine cells and neuro-epithelial bodies containing 5HT-like immunoreactivity was recorded within the lung. NPY-like immunoreactive nerve fibres were localised in the airway smooth muscle and surrounding the blood vessels. VIP-like immunoreactivity was revealed in single cells as well as in some nerve fibres and ganglia around the blood vessels and in the bronchial smooth muscle. SP-like IR was observed in nerve fibres located in the smooth muscle of the airways, surrounding bronchi and bronchioli but not next to the intrapulmonary blood vessels. Their localisation both in cells and nerve fibres of the respiratory system suggests that they play a role in the regulatory function of the mouse respiratory tract, exerting their influence by endocrine, paracrine, neurosecretory pathways or a combination of all of these.
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PMID:Presence and distribution of 5HT-, VIP-, NPY-, and SP-immunoreactive structures in adult mouse lung. 930 50


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