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)

Digestion of human foreskin with collagenase and hyaluronidase disperses approximately 3.4 X 10(7) nucleated cells per gram of tissue, of which mast cells constitute 4.7%. These may be purified to 80% by use of density gradient centrifugation. The majority of mast cells (79%) measured between 9 and 13 micron in diameter, and the mean histamine content was 4.6 pg/cell. Viability was demonstrated by trypan blue exclusion by 93% of the cells and the low spontaneous histamine secretion of less than 7% in functional studies. Anti-IgE released up to 17.5% of cell-associated histamine within 5 to 7 min. Calcium ionophore-induced release was optimal with 0.3 microM A23187 when 28.6% histamine was released. Unlike human lung mast cells, skin mast cells released histamine in response to compound 48/80 and poly-L-lysine. This release, which was complete within 20 sec, was totally dependent on intact glycolysis and oxidative phosphorylation and partially dependent on extracellular calcium. The same characteristics were observed with secretion induced by substance P and morphine. The weak activity of eledoisin and physalaemin suggests that the substance P receptor, like that of the rat mast cell, is not of the classical types described for smooth muscle. Morphine-induced secretion was partially blocked by naloxone in a manner not compatible with competitive antagonism at a classical opioid receptor. The sensitivity of skin mast cells to nonimmunologic stimulation clearly distinguishes them from mast cells of the lung and lymphoid tissues and provides evidence of functional heterogeneity within human mast cells.
 ...
PMID:Human skin mast cells: their dispersion, purification, and secretory characterization. 243 32

The effects of close intra arterial injection of substance P (SP) and the interaction of SP with opioid peptides, have been studied on mesenteric blood flow in the anaesthetized dog. Injection of SP into the superior mesenteric artery caused a dose dependent increase in mesenteric blood flow. This effect was enhanced by pretreatment with the alpha 2 adrenergic antagonist yohimbine. The action of SP was significantly reduced by pretreatment with muscarinic and nicotinic cholinergic, dopamine and histamine (H1) receptor antagonists. Beta adrenergic, histamine (H2) and opiate receptor antagonists did not influence the action of SP. Pretreatment with tetrodotoxin partially inhibited the effect of SP, indicating that as well as a neurogenic action, it has a direct action on the vascular smooth muscle. The effect of SP was enhanced by D-Met2-NleS5-enkephalinamide, a delta opiate receptor agonist. The actions of D-Met2-NleS5-enkephalinamide were abolished by pretreatment with hexamethonium, partially abolished by naloxone but were unaffected by atropine. The mu opiate receptor agonist, D-Met2-Pro5-enkephalinamide, inhibited the effects of SP.
 ...
PMID:Mechanism of "substance P": on mesenteric blood flow; interactions with opioid peptides. 244 93

Opioid drugs have been shown to inhibit neurogenic plasma exudation in skin by a presynaptic mechanism. We determined whether a similar inhibitory effect operates in the airways of anesthetized guinea pigs in vivo with the use of Evans blue dye as a marker of plasma leakage. Stimulation of the vagus nerve significantly increased leakage of dye in trachea and main bronchi (by approximately 300 and 600%, respectively). Similar increases in leakage were seen in the presence of atropine and propranolol. Morphine (1-30 mg/kg iv) inhibited leakage in a dose-related manner with complete inhibition in the trachea at a dose of 30 mg/kg. The inhibition was blocked by the opioid receptor-antagonist naloxone (1 mg/kg iv). Intravenous substance P significantly increased leakage but was not inhibited by morphine. We conclude that morphine inhibits neurogenic plasma leakage by presynaptic inhibition of release of neuropeptides from sensory nerve endings. If similar mechanisms are operative in human airways, inhibition of neurogenic plasma leakage by opioid drugs devoid of central effects may be of value in the therapy of asthma.
 ...
PMID:Neurogenic plasma extravasation: inhibition by morphine in guinea pig airways in vivo. 246 90

1. Opioid receptors have been demonstrated on sensory fibres in the vagus nerve. Non-cholinergic (NC) neural bronchoconstriction in guinea-pig is due to release of neuropeptides from sensory nerve endings. We have therefore studied the effect of opioids on this NC bronchoconstriction in the anaesthetized guinea-pig. 2. Bilateral vagal stimulation (5 V, 5 ms, 10 Hz) caused reproducible bronchoconstriction in guinea-pigs which was reduced by atropine (1 mg kg-1), but the NC component was unaffected by hexamethonium (10 mg kg-1). 3. NC bronchoconstriction was reduced by morphine in a dose-dependent manner (ED50 = 132 micrograms kg-1 with a maximal inhibition of 79 +/- 2.1% at 1 mg kg-1). Yohimbine (0.5 mg kg-1) did not alter the inhibitory effect of morphine (1 mg kg-1). 4. The inhibitory effect of morphine was completely reversed by naloxone (1 mg kg-1) which had no effect on NC bronchoconstriction. Propranolol (1 mg kg-1) significantly increased the NC bronchoconstrictor response but did not significantly alter the inhibition by morphine. 5. The selective mu-opioid receptor agonist Tyr-(D-Ala)-Gly-(N-Me-Phe)-Glyol (DAGOL) was significantly more potent than morphine with an ED50 of 5.4 micrograms kg-1 and complete inhibition at 100 micrograms kg-1. The delta-agonist Tyr-(D-Pen)-Gly-Phe-(D-Pen) (DPDPE) was less potent than DAGOL with an ED50 of 28 micrograms kg-1 and a maximal inhibition of only 50 +/- 5% at 100 micrograms kg-1. The delta-agonist Tyr4D-Pen)-Gly-Phe-D-Pen) (DPDPE) was less potent than DAGOL with an ED5o of 28pgkg-1 and a maximal inhibition of only 50 + 5% at lOOPgkg- . The Kappa-receptor agonist, U-50,488H had no inhibitory effect on the NC bronchoconstrictor response. 6. The bronchoconstrictor responses to exogenous substance P (25 pgkg- 1) or acetylcholine (25 pg kg- 1) were unaffected by morphine (500 pg kg- 1). 7. We conclude that opioids inhibit the NC bronchoconstrictor response to vagal stimulation via an action on mu-opioid receptors localized to sensory nerve endings in the airway.
 ...
PMID:Opioid modulation of non-cholinergic neural bronchoconstriction in guinea-pig in vivo. 246 5

An in vitro model system for analysis of presynaptic inhibitory actions of spinal opioids has been applied. Embryonic sensory neurons derived from chick dorsal root ganglia were grown in primary cell culture, and the release of substance P was evoked by electrical field stimulation during exposure to drugs with well-demonstrated affinity for opioid receptors. This allowed a pharmacologic characterization of the inhibitory actions of specific opioid agonists on the release of substance P as measured by radioimmunoassay (RIA). Sufentanil (0.5 microM), a high affinity mu receptor agonist, U-50,488H (25 microM), a selective kappa receptor agonist, and morphine (10 microM), an agonist with high affinity for mu and delta receptors, inhibited the evoked release of substance P by approximately 60%, 40%, and 50%, respectively. For sufentanil the response was demonstrated to be dose-dependent. As is the case for its analgesic action in vivo, morphine was approximately 50-fold less potent than sufentanil on a molar basis in this assay. The actions of sufentanil, U-50-488H and morphine were mimicked by the endogenous opioid peptide met-enkephalin, and its stable synthetic analog D-ala2-met5-enkephalinamide (DAME). Naloxone (25 microM), an opioid receptor antagonist, blocked the inhibitory action of sufentanil (0.5 microM), morphine (5 microM), and DAME (5 microM), but not U-50,488H (10 microM). The action of U-50,488H was partially blocked by the antagonist naltrexone (25 microM). Stereo-selectivity of agonist action was confirmed by the failure of dextrorphan (50 microM), an inactive opioid isomer, to inhibit the release of substance P.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Sufentanil, morphine, met-enkephalin, and kappa-agonist (U-50,488H) inhibit substance P release from primary sensory neurons: a model for presynaptic spinal opioid actions. 246 89

Capsaicin has been shown to evoke the release of substance P (SP) from small diameter primary afferent fibers. Using an in vivo perfusion of the rat spinal cord, this study examined the pharmacology of opioid receptor systems which modulate the capsaicin-evoked release of SP. The addition of capsaicin (200 microM) to the perfusate raised SP-like immunoreactivity (SP-LI) from resting levels of 31 +/- 5 to 74 +/- 14 pg/ml or an increase of 139% above the baseline. Using high pressure liquid chromatography (HPLC) the identity of the released SP-LI was determined to coelute primarily with authentic SP or the oxidized form of SP. Opioid receptor agonists were added to the perfusate and their ability to inhibit capsaicin-evoked release of SP-LI was assessed. Morphine (10-100 microM), DAGO (1-100 microM), DPLPE (10-100 microM), but not U50488H (100 microM) produced a dose-dependent reduction in the capsaicin-evoked release of SP-LI. Pretreatment with the opioid receptor antagonist naloxone (1 mg/kg, IP) had no effect on the basal or capsaicin-evoked release of SP-LI. Naloxone pretreatment was able to antagonize completely the opioid-produced inhibition of capsaicin-evoked SP-LI release. These data indicate that the release of SP from primary afferent fibers can be modulated by the activation of mu or delta but not kappa opioid receptors. Further, these data support the hypothesis that spinally administered mu and delta opioid agonists may produce their antinociceptive effect through the presynaptic inhibition of neuropeptide release from small diameter primary afferent fibers.
 ...
PMID:Opioid modulation of capsaicin-evoked release of substance P from rat spinal cord in vivo. 248 63

Based on the observed membrane structures of substance P, physalaemin, and eledoisin, preferred conformations, orientations and accumulations of 13 mammalian neurokinins and non-mammalian tachykinins were estimated and compared with pharmacologic and selective binding data taken from the literature. Principal site affinities and relative affinities supported the view that neurokinins bind to three principal mammalian sites: the NK-1 (preferring substance P), the NK-2 (preferring neurokinin A), and the NK-3 site (preferring neurokinin B). Strong hydrophobic membrane interaction of the C-terminal message segment as a perpendicularly oriented alpha-helical domain correlated with NK-1 selection. Electrostatic accumulation of the peptide at the anionic fixed charge layer of the membrane without hydrophobic interaction through a helix correlated with NK-2 preference. Electrostatic repulsion by the anionic fixed charge layer correlated with NK-3 selection. Thus, neurokinin receptor selection is guided by the same principles as opioid receptor selection. Membrane catalysis of specific agonist--receptor interactions may prove to be a quite general phenomenon, and the membrane structure of a peptide more important for its structure--activity relationship than its crystal structure or its mixture of conformers in solution or in vacuo.
 ...
PMID:Membrane-assisted molecular mechanism of neurokinin receptor subtype selection. 282 84

A photoreactive (D-Ala2, p-N3-Phe4-Met5)enkephalin derivative was prepared, iodinated with carrier-free 125I, and then purified by high-performance liquid chromatography. The purified radioactive photoprobe was monoiodinated at the amino terminal tyrosine residue. This radioactive photoprobe was used to photoaffinity label membranes prepared from the rat brain (minus cerebellum) and the spinal cord. The photolabeled membranes were analyzed by sodium dodecyl sulfate gel electrophoresis. A 46,000-Da protein was specifically photolabeled in these membrane preparations. The photolabeling of this protein was inhibited by peptides related to enkephalin but not by unrelated substance P or gastrin tetrapeptide. A concentration-dependent inhibition of the photolabeling of the 46,000-Da protein was observed in the presence of competing ligands specific for the mu-, delta-, and kappa-opioid receptors. These data demonstrate that the radioactive photoprobe labels the mu-, delta-, and kappa-opioid receptors. Although there is no evidence available to show that the 46,000-Da protein is identical in all the cases, our data strongly suggest that it is a binding protein common to all of the opioid receptor subtypes.
 ...
PMID:Photoaffinity labeling of opioid receptor of rat brain membranes with 125I(D-Ala2, p-N3-Phe4-Met5)enkephalin. 303 63

The effect of a potent opioid agonist, [D-Met2, Pro5]-enkephalinamide was investigated on two responses involving capsaicin-sensitive afferent neurones, namely, atropine-resistant contractions of the guinea-pig bronchus evoked by electrical field stimulation and the nociceptor stimulation to intraarterial injections of acetylcholine or capsaicin into the vascularly isolated rabbit ear. The hypotheses to be tested were whether (a) opioid receptor activation may inhibit mediator release from primary afferent neurones and (b) the opioid could exert an analgesic effect at a peripheral site of action. Non-cholinergic contractions of the guinea-pig isolated main bronchi due to electrical stimulation were concentration-dependently inhibited by [D-Met2, Pro5]-enkephalinamide (10 nM-1 microM). This effect was abolished by naloxone (1 microM). Naloxone alone induced no change in the stimulation-evoked contractions of the bronchus, indicating that no endogenous opioid control was present. Substance P and neurokinin A induced bronchial contractions that were not influenced by [D-Met2, Pro5]-enkephalinamide. This indicates that [D-Met2, Pro5]-enkephalinamide inhibits electrically-evoked bronchial contractions by reduced mediator release from capsaicin-sensitive sensory nerve endings, since these contractions are most probably brought about by tachykinins, released from afferent neurones. Capsaicin-induced bronchial contractions were in contrast to electrical stimulation not influenced by [D-Met2, Pro5]-enkephalinamide which suggests a different site of action. The activation of sensory neurones in the rabbit ear by i.a. injection of acetylcholine and capsaicin was not reduced under infusion of [D-Met2, Pro5]-enkephalinamide (1 and 10 microM) or lofentanil (1 and 10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Peripheral effects of opioid drugs on capsaicin-sensitive neurones of the guinea-pig bronchus and rabbit ear. 368 97

The tripeptides SD-34 and SD-25 induced atropine-, guanethidine-, antihistaminics-resistant but naloxone-sensitive contractions of isolated rat distal colon. They appeared to act on an opioid receptor, probably of the mu subtype, distinct from those for methionine enkephalin and morphine, because the pA2 values of naloxone for the peptides were similar to those for mu-agonists but different from those for methionine enkephalin and morphine, and because the peptides caused contractions of colon that had been desensitized to morphine. Mr 2266, a supposed kappa-antagonist, inhibited the actions of the peptides, ethylketocyclazocine and dynorphin at concentrations much lower than those inhibiting the actions of methionine enkephalin and morphine. Thus these peptides seem to act on the mu- and/or kappa-receptors. The actions of the tripeptides were inhibited by methysergide and methylergometrine, but not by the 5-HT2 antagonist ketanserin, and were not affected by 5-HT or substance P autodesensitization . Thus their actions do not seem to involve 5-HT, histamine, ACh or substance P. It seems likely that the tripeptides, through opioid receptors, directly activate the muscle, or remove some inhibitory modulation of myogenic activity, thus causing contractions.
 ...
PMID:Tripeptides acting on opioid receptors in rat colon. 620 30


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