Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A recently developed series of highly selective and systemically active delta-agonists such as Tyr-X-Gly-Phe-Leu-Thr(OtBu), with X = D.Ser (OtBu) in BUBU and X = D.Cys(StBu) in BUBUC, and complete inhibitors of enkephalin metabolism (Kelatorphan, RB 38 A, PC 12) have enabled the major role played by mu-opioid receptors in supraspinal analgesia to be demonstrated. This is in agreement with the results of in vivo mu-receptor occupancy measured by taking into account the cross-reactivity of the delta-ligands for mu-sites. In contrast, mu and delta binding sites seem to act independently to control pain at the spinal level. Strong analgesic effects, especially in arthritic rats, can also be obtained by complete protection of tonically or phasically released endogenous enkephalins with mixed inhibitors such as RB38A. Chronic icv administration of the mu agonist DAGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the delta agonist, DSTBULET or with RB 38 A. Moreover, mixed inhibitors did not induce any significant respiratory depression. All these data emphasize the interest in developing delta-agonists and mixed inhibitors with appropriate bioavailability for clinical evaluation.
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PMID:Novel approaches in the development of new analgesics. 196 53

1. Opioid receptors in the neonatal rat spinal cord have been characterized by measurements of ligand binding to crude membrane fractions and by functional tests on the nociceptive spinal response in a spinal cord-tail preparation in vitro. 2. There were high affinity binding sites for [3H]-[D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGOL), [3H]-U69593, and [3H]-ethylketocyclazocine (EKC) on spinal cord membranes from neonatal rats. Hill slopes for binding of [3H]-DAGOL and [3H]-U69593 were close to unity. The Hill slope for binding of [3H]-EKC was less than unity, even after its interactions at mu-receptors had been blocked with 100 nM unlabelled DAGOL. Binding sites for [3H]-[D-Pen2, D-Pen5]enkephalin (DPDPE) could not be detected. 3. In competition assays U50488 was as potent as PD117302 and U69593 in competition for either [3H]-U69593 or [3H]-EKC binding sites. Hill slopes for a range of competing ligands at [3H]-DAGOL or [3H]-U69593 sites were close to unity. Hill slopes for competition at [3H]-EKC sites were less than one. 4. In the spinal cord-tail preparation from neonatal rats, opioid receptor agonists depressed spinal nociceptive responses evoked by application of capsaicin or heat to the tail. The order of potency was DAGOL greater than U69593 = PD117302 greater than morphine greater than U50488 = [D-Pen2, L-Pen5]enkephalin (DPLPE). 5. The antagonist naloxone was about equally potent against DAGOL, morphine and DPLPE, and about ten times less potent against U69593 and PD117302. The effects of U50488 were much less sensitive to blockade by naloxone than the effects of PD11703 or U69593. The Kappa antagonist, nor-binaltorphimine was equipotent against all three Kappa agonists. 6. The absence of delta-binding sites, and the low potency and relatively high sensitivity to naloxone suggest that DPLPE could be working at mu-receptors in the neonatal rat spinal cord. 7. The binding assays show that U50488 has the same affinity as PD1 17302 and U69593 for Kappa-receptors, yet it was less effective in the depression of nociceptive responses. This may be because U50488 has a relatively low efficacy at Kappa-receptors. It is possible that at high concentrations U50488 activates receptors not affected by other Kappa-ligands. These additional receptors may be non-opioid receptors (hence the insensitivity to naloxone), or they could be a subtype of Kappa-opioid receptor.
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PMID:Opioid receptor ligands in the neonatal rat spinal cord: binding and in vitro depression of the nociceptive responses. 215 45

1. Cardiac output, arterial pressure, heart rate, systemic vascular conductance, respiratory rate and arterial blood PO2 and PCO2 were measured in unanaesthetized rabbits. Haemorrhage was simulated by inflating a cuff placed around the inferior vena cava so that cardiac output fell at a constant rate of about 8% of its resting value per min. 2. The effects of drug treatments on resting haemodynamic and respiratory variables, and on the haemodynamic response to simulated haemorrhage, were tested. The treatments were; 4th ventricular (-)-naloxone HCl (10-100 nmol), 4th ventricular H-Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAMGO; 30-300 pmol), and i.v. morphine sulphate (0.5-5.0 mumol kg-1). The interactions of graded 4th ventricular doses of naloxone (3-100 nmol) with the actions of DAMGO (100-300 pmol) on these responses were also assessed. 3. After sham treatments, the circulatory response to simulated haemorrhage had two phases. During the first compensatory phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only about 7 mmHg. A second decompensatory phase supervened when cardiac output had fallen by about 50%. At this point systemic vascular conductance rose abruptly and arterial pressure fell to less than or equal to 40 mmHg. 4. Low 4th ventricular doses of naloxone (10-30 nmol) and DAMGO (30-100 pmol) had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of naloxone (30-100 nmol) and DAMGO (100-300 pmol) prevented the decompensatory phase. These high doses of naloxone and DAMGO lowered resting heart rate without affecting the other haemodynamic or respiratory variables. 5. Low doses of i.v. morphine (0.5-1.Spumolkg-1) also had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of morphine (1.5-5.Opmol kg 1) abolished the decompensatory phase. These high doses caused respiratory depression without affecting the resting haemodynamic variables. 6. The prevention of circulatory decompensation by high doses of DAMGO was reversed by 3-10nmol of naloxone in 3 out of 4 rabbits and by 10-30 nmol of naloxone in all 4 rabbits. The decompensatory phase was, however, prevented by the combined high doses of DAMGO (100-300pmol) and naloxone (30-100 nmol). 7. These findings provide strong evidence that activation of mu-opioid receptors in the central nervous system abolishes circulatory decompensation during acute reduction of central blood volume in conscious rabbits. This effect does not appear to be due to activation of arterial chemoreceptors or to a non-specific increase in sympathetic vasoconstrictor drive, since respiratory depression and hypertension were not observed after 4th ventricular doses of DAMGO which abolished circulatory decompensation. Our results also provide indirect confirmation of our previous finding that naloxone acts to prevent circulatory decompensation by an antagonist action at central delta-receptors.
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PMID:Effects of mu-opioid receptor agonists on circulatory responses to simulated haemorrhage in conscious rabbits. 216 31

1. We have compared the ability of various tachykinins and selective tachykinin receptor agonists to induce contraction of the endothelium-denuded rabbit pulmonary artery (RPA) and hamster trachea (HT) and have estimated the affinity of some newly developed NK2 selective antagonists in the same tissues. 2. In confirmation of previous findings, experiments with the agonists indicated that NK2 receptors are the main if not the sole mediators of the response to tachykinins in both RPA and HT. No evidence for significant degradation of neurokinin A (NKA) was found in either tissue when experiments were repeated in the presence of a mixture of peptidase inhibitors (thiorphan, captopril and bestatin, 1 microM each). 3. The peptide antagonists tested were: Peptide I = [Tyr5, D-Trp6,8,9, Arg10]-NKA(4-10); Peptide II = [Tyr5, D-Trp6,8,9, Arg10]-NKA(3-10); Peptide III = Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2. The three peptides produced a concentration-dependent rightward shift of the concentration-response curve to NKA in both RPA and HT with no significant depression of the maximal response attainable. The slopes of the Schild plots were not significantly different from unity, indicating a competitive antagonism. Peptides I and II were about 100 times more potent in the RPA than in the HT, while Peptide III was about 100 times more potent in the HT than RPA. 4. The pA2 values obtained in these two tissues with the three antagonists were not significantly different when tested in the absence or presence of peptidase inhibitors, or when a selective NK2 receptor agonist, [beta Ala8]-NKA(4-10) was used instead of NKA. Similar pA2 values were obtained after 15 or 90min of incubation with the antagonists. Peptides I, II and III had no inhibitory effect on contractions produced by noradrenaline in the RPA or by carbachol in the HT. 5. Peptides I, II and III showed weak or no antagonistic activity toward the vasodilatator effect of substance P in the dog carotid artery (NK, receptor-mediated) or toward the contractile effect of neurokinin B in the rat portal vein (NK3 receptor-mediated). 6. These results provide pharmacological evidence for heterogeneity of NK2 receptors in the RPA and HT. The NK2 receptors present in these tissues are not discriminated by natural tachykinins or selective agonists, but are recognized with very different affinity by NK2 receptor antagonists.
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PMID:Competitive antagonists discriminate between NK2 tachykinin receptor subtypes. 216 37

1. Actions of the neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2) and its derivative YGG-FMRFamide (Tyr-Gly-Gly-Phe-Met-Arg-Phe-NH2) on Ca2+ current were examined in identified, voltage-clamped neurones in the abdominal ganglion of Aplysia californica. 2. 'Puffed' application of either peptide at concentrations of 1-50 microM was followed by a transient partial suppression of pharmacologically isolated inward Ca2+ current elicited by a depolarizing step. At 20 degrees C, suppression was maximal 10-25 s following the brief puff of peptide, and lasted up to 90 s. Bath application of peptide had a steady suppressing effect, showing little if any desensitization. 3. Alternative sources of inward current suppression were ruled out, indicating that application of FMRFamide or YGG-FMRFamide produces a true decrease in Ca2+ current, rather than enhancement of possible contaminating outward (K+, H+ or Cl-) currents. 4. FMRFamide and YGG-FMRFamide were equally effective in suppressing Ca2+ current (apparent dissociation constant, KD* approximately 10 microM). However, only 30-50% of the total Ca2+ current elicited by voltage steps to above +10 mV appeared to be susceptible to suppression by even saturating concentrations of peptide. This, as well as a reduced effect of the peptides on Ca2+ current which was observed at potentials below +10 mV, may perhaps result from the presence of more than one class of Ca2+ channels, only one of which is sensitive to FMRFamide. 5. FMRFamide eliminated a constant fraction of Ca2+ current at all potentials above +10 mV, and had no direct effect on activation or inactivation of the remaining current. This behaviour is consistent with reduction in the number of functional Ca2+ channels by the peptide. 6. Suppression of Ca2+ current produced a concomitant depression of Ca2+-dependent K+ current, which was shown previously to be insensitive to FMRFamide when activated by direct ionophoretic injection of Ca2+ into the cell. 7. The effect of FMRFamide on Ca2+ current was normal following interference with or activation of known second-messenger systems, those involving adenosine 3',5'-cyclic monophosphate (cyclic AMP), cyclic GMP, Ca2+, inositol trisphosphate and protein kinase C. 8. Suppression of Ca2+ current by FMRFamide appeared to be mediated by the same receptor as enhancement by the peptide of K+ current resembling IK(S) (K+ current suppressed by serotonin), an effect seen in most of the same cells. Both effects of FMRFamide were mimicked by injection of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) into the cell, suggesting that the peptide may exert its effects by activating a guanosine 5'-triphosphate (GTP)-binding protein
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PMID:Suppression of calcium current by an endogenous neuropeptide in neurones of Aplysia californica. 244 95

Prolylendopeptidase activity was increasingly depressed with time from 6 to 24 hr after the start of sensitization in the delayed hypersensitive guinea pig skin lesion induced by bovine gamma-globulin as an antigen. The remarkably depressed activity of the enzyme in the violently inflamed skin began to be restored slowly 48 hr after sensitization, and its activity was ultimately recovered to the original level by 504 hr after a single sensitization in vivo. Depression of the enzymatic activity is caused by a novel prolyendopeptidase inhibitor, whose amino acid composition is 7 Glu, 1 Ser, 2 Gly, 1 Ala, 2 Pro, and 1 Val, generated by inflammation.
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PMID:Depression of prolylendopeptidase activity in the delayed hypersensitive guinea pig skin lesion induced by bovine gamma-globulin. 247 52

Although point mutations usually lead to minor localized changes in protein structure, replacement of conserved Pro-76 with Gly in iso-2-cytochrome c induces a major conformational change. The change in structure results from mutation-induced depression of the pK for transition to an alkaline conformation with altered heme ligation. To assess the importance of position 76 in stabilizing the native versus the alkaline structure, the equilibrium and kinetic properties of the pH-induced conformational change have been compared for normal and mutant iso-2-cytochrome c. The pKapp for the conformational change is reduced from 8.45 (normal iso-2) to 6.71 in the mutant protein (Gly-76 iso-2), suggesting that conservation of Pro-76 may be required to stabilize the native conformation at physiological pH. The kinetics of the conformational change for both the normal and mutant proteins are well-described by a single kinetic phase throughout most of the pH-induced transition zone. Over this pH range, a minimal mechanism proposed for horse cytochrome c [Davis, L. A., Schejter, A., & Hess, G. P. (1974) J. Biol. Chem. 249, 2624-2632] is consistent with the data for normal and mutant yeast iso-2-cytochromes c: NH KH----N + H+ kcf in equilibrium kcb A NH and N are native forms of cytochrome c with a 695-nm absorbance band, A is an alkaline form that lacks the 695-nm band, KH is a proton dissociation constant, and kcf and kcb are microscopic rate constants for the conformational change. The Gly-76 mutation increases kcf by almost 70-fold, but kcb and KH are unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Replacement of a conserved proline and the alkaline conformational change in iso-2-cytochrome c. 255 30

A mature sacrococcygeal in vitro spinal preparation from the rat has been used to demonstrate effects of neutral amino acids and their antagonists. gamma-Aminobutanoate (GABA), glycine and taurine (0.5-5 mM) produced dose-dependent depression of spontaneous paroxysmal activity generated in Mg2+ -free medium. The depressant effect of GABA was antagonised selectively by picrotoxin (25-50 microM) and the depressant effects of glycine and taurine were antagonised selectively by strychnine (0.2 microM). Glycine (0.5-5 mM) had a dose-dependent depolarizing action which was present at the central ends of isolated ventral roots. gamma-Aminobutanoate and taurine, had only weak depolarizing actions on ventral root fibres. Depolarizing responses to glycine showed a marked fading. Reduction in the fading appeared to be responsible for a paradoxical potentiation of glycine-induced depolarizations, which occurred in the presence of strychnine (0.2-2 microM). Strychnine (2-10 microM), picrotoxin (10-50 microM) or bicuculline (10 microM) had little or no effect on the amplitude, duration or latency of the monosynaptic component of ventral root reflexes evoked by supramaximal stimulation of dorsal roots (DR-VRP). However all three antagonists introduced slow, NMDA receptor mediated, components to these ventral root potentials. Picrotoxin and bicuculline, but not strychnine, reversibly depressed the dorsal root potential evoked from an adjacent dorsal root (DR-DRP). The depressant actions of 2-amino-5-phosphonopentanoate (AP5), kynurenate and 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) revealed both NMDA and non-NMDA receptor mediated components in the dorsal root potential.
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PMID:Effects of depressant amino acids and antagonists on an in vitro spinal cord preparation from the adult rat. 276 79

Metalloendoprotease activity that was sensitive to the metal chelator 1,10-phenanthroline and to synthetic dipeptide substrates of the enzyme was detected in homogenates of dorsal root ganglia (DRG) and spinal nerve from the bullfrog. Exposure of an intact in vitro preparation of DRG and spinal nerves to 1,10-phenanthroline led to a dose-dependent depression in the accumulation of fast-transported 3H-labeled protein proximal to a nerve ligature. In nonligated preparations, the chelator treatment reduced the amount of transported protein entering the nerve; no marked effect on the transport rate was observed. Exposure of a desheathed region of spinal nerve to 1,10-phenanthroline, while DRG were maintained in control medium, resulted in a slight depression of fast transport. This effect was not dose dependent over the range that produced a dose response when both DRG and spinal nerve were exposed to the drug. Treatment of DRG and spinal nerve with the metalloendoprotease substrate analogues carbobenzoxy (CBZ)-Ser-Leu-amide or CBZ-Gly-Leu-amide inhibited fast axonal transport, whereas treatment with CBZ-Gly-Gly-amide, which is not a substrate, had no detectable effect on transport. Selective exposure of desheathed nerve trunk to CBZ-Ser-Leu-amide inhibited fast transport, but the effect was less marked than when DRG and nerve trunk were treated. Although previous studies have focused on the role of metalloendoprotease activity in exocytosis, the present data suggest that the enzyme may also be involved in earlier stages of intracellular transport.
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PMID:Metalloendoprotease inhibitors block fast axonal transport. 278 54

1 The effects of opioids on synaptic transmission in cat sacral parasympathetic colonic ganglia were studied in vitro, using intracellular electrophysiological techniques. Electrical stimulation of the pelvic nerve evoked fast excitatory postsynaptic potentials (e.p.s.ps), which were blocked by hexamethonium and tetrodotoxin. 2 [D-Pen2, D-Pen5] enkephalin and [Met5]enkephalinamide, delta-opioid receptor agonists, caused concentration-dependent, reversible depression of fast e.p.s.ps, but had no effect on depolarizations evoked by pressure ejection of the nicotinic agonist 1,1-dimethyl-4-phenyl-piperazinium. Cell transmembrane potential and membrane input resistance were also unaffected. 3 U-50,488H, a kappa-opioid receptor agonist, had a very small depressant action while [D-Ala2, MePhe4, Gly-ol5] enkephalin, a mu-opioid receptor agonist, had no effect on fast e.p.s.p. amplitude. Neither compound affected cell transmembrane potential or membrane input resistance. 4 The inhibitory actions of [D-Pen2, D-Pen5] enkephalin were antagonized by both naloxone, an antagonist at each of the three opioid receptor types, and by ICI 174,864, an antagonist selective for delta-opioid receptors. 5 Naloxone and ICI 174,864 both also potentiated fast e.p.s.p. amplitude per se in 50% of cells tested. 6 It is concluded that exogenous opioids act at presynaptic delta-opioid receptors to inhibit sacral parasympathetic synaptic transmission in cat colonic ganglia in vitro. Furthermore, the effects of opioid antagonists alone, suggest that endogenous opioids may also be released by preganglionic nerve stimulation and so regulate the release of acetylcholine in these ganglia.
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PMID:Delta-opioid receptors mediate inhibition of fast excitatory postsynaptic potentials in cat parasympathetic colonic ganglia. 282 50


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