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)

Intrathecal (i.t.) injection of a kappa-opioid receptor agonist, ICI197067, caused a similar dose dependent depression of A delta and C fibre mediated nociceptive reflexes in renal sympathetic nerves due to supramaximal electrical stimulation of tibial nerves in anaesthetized dogs. A total dose of 8 mg i.t. abolished these reflexes. When administered into the 4th ventricle (i.c.v.) in a total dose range from 0.1-2.5 mg ICI197067 caused no respiratory depression; a total dose of 10 mg i.c.v. abolished both phrenic nerve activity and spontaneous respiration. The ED50 ratio of ICI197067 for depression of respiration (i.c.v.) and somatosympathetic reflexes (i.t.) is approximately 1.5:1 compared with 0.3:1 for fentanyl. ICI197067 i.c.v. caused a similar reduction in arterial pressure compare to fentanyl without comparable changes in heart rate. Thus in terms of cardiorespiratory depression and blockade of A delta and C fibre pathways kappa-opioid receptor agonists may be safer and more effective for producing spinal analgesia than mu-opioid receptor agonists.
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PMID:Effect of ICI197067, a kappa-opioid receptor agonist, spinally on A delta and C reflexes and intracerebrally on respiration. 827 59

1. The electrophysiological action of the mu-opioid receptor-preferring agonist D-Ala2, MePhe4, Met(O)5-ol-enkephalin (FK 33-824) on synaptic transmission has been studied in area CA3 of organotypic rat hippocampal slice cultures. 2. FK 33-824 (1 microM) had no effect on the amplitude of pharmacologically isolated N-methyl-D-aspartate (NMDA) or non-NMDA receptor-mediated EPSPs. 3. FK 33-824 (10 nM to 10 microM) reduced the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) that were elicited in pyramidal cells with local stimulation after pharmacological blockade of excitatory amino acid receptors. This effect was reversible, dose-dependent, and sensitive to naloxone and the mu-receptor antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP). FK 33-824 at 1 microM caused a mean reduction in the amplitude of the monosynaptic IPSP of 70%. 4. Neither delta- nor kappa-receptor-preferring agonists had any effect on excitatory or inhibitory synaptic potentials. 5. The disinhibitory action of FK 33-824 was blocked by incubating the cultures with pertussis toxin (500 ng/ml for 48 h) or by stimulation of protein kinase C with phorbol 12,13-dibutyrate (PDBu, 0.5 microM). 6. The depression of monosynaptic IPSPs by FK 33-824 was unaffected by extracellular application of the K+ channel blockers Ba2+ or Cs+ (1 mM each). 7. FK 33-824 produced a decrease in the frequency of miniature, action potential-independent, spontaneous inhibitory synaptic currents (mIPSCs) recorded with whole-cell voltage-clamp techniques, but did not change their mean amplitude. Application of the Ca2+ channel blocker Cd2+ (100 microM) or of nominally Ca(2+)-free solutions did not alter either the frequency and amplitude of mIPSCs or the reduction of mIPSC frequency induced by FK 33-824. 8. The effect of FK 33-824 on spontaneous mIPSCs was prevented by naloxone, and by incubation of cultures with pertussis toxin. 9. These results indicate that mu-opioid receptors decrease GABA release presynaptically by a G protein-mediated inhibition of the vesicular GABA release process, and not by changes in axon terminal K+ or Ca2+ conductances that are sensitive to extracellular Ba2+, Cs+ or Cd2+.
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PMID:Mechanism of mu-opioid receptor-mediated presynaptic inhibition in the rat hippocampus in vitro. 830 42

Until recently only the racemic mixture of ketamine was available for anesthesia. Little is known, of the central nervous effects of the pharmacological more potent S(+)-isomer. In order to evaluate the effects on respiration, the electroencephalographic activity and on the somatosensory evoked potential (SEP), increasing doses of S(+)-ketamine (2-5-10-20 mg/kg) were given to trained and awake canines (n = 10) at 10 minutes interval. To demask any opioid-receptor mediated effect, the highly selective mu-antagonist naltrexone or the highly selective delta-antagonist naltrindole (NTI) was given after S(+)-ketamine. S(+)-ketamine depressed respiration in a dose-related manner (PaO2 decrease, PaCO2 increase). Hypoxia was fully reversed by NTI and naltrexone; however hypercapnia was only partly reversed. S(+)-ketamine induced a dose-related increase of power in the theta-band (3-8 Hz) with little increase of power in the alpha-domain (8-13 Hz). Both these changes were reversed by NTI and naltrexone. Compared to control, low doses (2-5 mg/kg) increased power (p < 0.05) in the beta-(13-30 Hz) and decreased power (p < 0.05) in the delta-(0.5-3 Hz) band. These effects changed with higher doses (5-10 mg/kg). When compared to control, power in the delta-domain was significantly higher (p < 0.05), while power in the beta-band decreased significantly following 20 mg/kg of S(+)-ketamine. NTI was capable to reverse all these effects, however, naltrexone was not. In the SEP, S(+)-ketamine induced a dose-related increase in peak latency and a depression of amplitude of more than 50% when compared to control. Latency changes and amplitude height was only partly restored by both antagonists. The present results corroborate the connotation, that the central effects of the S(+)-isomer of ketamine are related to the opioid delta- and mu-receptor. The respiratory depression may be of importance when S(+)-ketamine is used (in very high doses). The S(+)-isomer induced hypersynchronisation in the EEG, suggests a deep plane of anesthesia; the pronounced blockade of nociceptive stimuli in the sensory nervous pathways suggests an analgesic effect which is partly mediated by the opioid receptor.
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PMID:Opioid receptors-mediated respiratory effects and antinociception after S(+)-ketamine. 831 Jul 88

Cholecystokinin octapeptide (CCK-8) is reported to antagonize the analgesic effect produced by mu- and kappa- but not delta-opioid agonist in spinal cord. However, the mechanisms of interaction remain obscure. In the present study, whole-cell patch-clamp recording was performed on acutely isolated rat dorsal root ganglion (DRG) neurons to evaluate the effects of the highly specific mu-opioid agonist ohmefentanyl and the delta-opioid agonist DPDPE on voltage-gated calcium channels and the possible interaction between CCK-8 receptor and mu- or delta-opioid receptor. The results indicated that ohmefentanyl, but not DPDPE, can suppress the voltage-gated calcium currents elicited in DRG neurons, an effect readily reversed by naloxone or by the antiopioid peptide CCK-8. The effect of CCK-8 can in turn be abolished by the CCK-B receptor antagonist L365,260. CCK-8 used by itself has no enhancing effect, but rather a depressant effect, on calcium currents. However, used simultaneously with ohmefentanyl, CCK-8 shows a clear-cut reversal of depression of the mu-opioid. We conclude that the depressant effect produced by mu-opioid on voltage-gated calcium current in DRG neurons can be antagonized by CCK-8 through CCK-B receptor located in the same neuron. The delta-opioid DPDPE has no direct effect on the voltage-gated calcium current in DRG neurons.
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PMID:Cholecystokinin octapeptide reverses mu-opioid-receptor-mediated inhibition of calcium current in rat dorsal root ganglion neurons. 853 Oct 95

1. Whole-cell calcium currents were recorded from visually identified inhibitory interneurones located in stratum radiatum (near the border with stratum lacunosum-moleculare) of area. CA1 in rat hippocampal slices. Current-voltage (I-V) relationships in relatively well-clamped neurones showed that inward current activated between -50 and -40 mV (holding potential, -80 mV) and was maximal near -10 mV. Currents showed little inactivation over the course of 85 ms steps, and were completely blocked by removal of Ca2+ or addition of Cd2+. Prominent low-threshold currents were not observed under these conditions. 2. The calcium channels contributing to whole-cell currents in interneurones were examined using selective channel antagonists. The selective N-type calcium channel blocker omega-conotoxin GVIA (omega-CgTX-GVIA; 10 microM) irreversibly blocked 23.2 +/- 2.8% of whole-cell currents. The P/Q-type antagonist omega-agatoxin IVA (omega-Aga-IVA; 1-5 microM) blocked 10.4 +/- 3.3% of whole-cell currents. Block by omega-Aga-IVA was highly variable, ranging from 0 to 30%. The less selective conotoxin, omega-conotoxin MVIIC (omega-CTX-MVIIC; 5 microM) blocked 31.0 +/- 2.7% of whole-cell currents. The selective L-type channel antagonist nifedipine (20 microM) blocked 27.5 +/- 3.5% of whole-cell currents. 3. Whole-cell calcium currents were reversibly inhibited by the selective GABA(B) receptor agonists (+/-)-baclofen or CGP 27492 (1-3 microM; 18.9 +/- 1.4%). This inhibition was reversed or prevented by the selective GABAB receptor antagonist CGP 55845A (1 microM). Inhibition of inward current activated by voltage ramps was voltage dependent, being greatest near -10 mV, and less pronounced at more positive or negative potentials. Inhibition of calcium currents by GABAB receptor agonists was accompanied by an apparent change in the kinetics of whole-cell currents consistent with a slowing of the rate of activation. CGP 27492 depressed calcium currents by 16.1 +/- 1.9% before application of omega-CgTX-GVIA, and by 3.9 +/- 2.0% after application of omega-CgTX-GVIA in the same cells (P < 0.005), consistent with preferential block of N-type calcium channels. 4. Neither adenosine (200 microM) nor the selective mu-opioid receptor agonist Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO; 2 microM) inhibited calcium currents. Similarly, CGP 27492, but not adenosine or DAMGO, induced an outward current (at - 70 mV) consistent with activation of inwardly rectifying potassium channels. 5. These results indicate that hippocampal inhibitory neurones located in stratum radiatum possess multiple calcium channel subtypes, including N-type, L-type, and at least two other types of high-threshold channels. Activation of GABAB receptors (but not adenosine or mu-opioid receptors) preferentially inhibits N-type channels in these neurones. Similar inhibition occurring in the terminals of interneurones could contribute to depression of inhibitory synaptic transmission by activation of GABAB autoreceptors.
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PMID:High-threshold Ca2+ currents in rat hippocampal interneurones and their selective inhibition by activation of GABA(B) receptors. 873 May 88

The aim of this study was to investigate the possible involvement of the mu-opioid system on the learned-helplessness paradigm, an experimental model of depression, in rats. In this test, rats were first exposed to inescapable foot-shocks (IS); 48 h later, they were submitted to a daily shuttle-box session (30 trials) for 3 consecutive days. Avoidance responses, escape failures and animal activity during each intertrial interval were recorded. Twice daily injections of morphine (0.25-8 mg/kg per day, SC), a mu-opioid agonist, reduced the increased escape failures induced by IS, as did tricyclic antidepressants. Significantly higher intertrial activity was observed in rats treated with morphine (2-8 mg/kg per day) compared with their associated control groups. Naloxone (1 and 2 mg/kg, IP), a mu-opioid antagonist, injected 10 min before each shuttle-box session impaired escape behavior in non-stressed rats and worsened the escape deficit induced by IS. Morphine-induced improvement of escape behavior and increase in intertrial activity were clearly reversed by a low inactive dose of naloxone (0.5 mg/kg). These results suggest that mu-opioid receptor mediation is involved in the deleterious effects of uncontrollable stress.
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PMID:Effects of morphine, naloxone and their interaction in the learned-helplessness paradigm in rats. 874 57

Chronic pain remains a problem because it is often misdiagnosed and undertreated. Adverse effects and safety concerns associated with many analgesics have limited the use of these agents and contributed to the undertreatment of pain. With regard to the pharmacologic agents most commonly used to manage pain, centrally acting analgesics (e.g., morphine, codeine) are associated with respiratory depression, tolerance, and dependence, and most nonsteroidal anti-inflammatory drugs (NSAIDs) produce adverse gastrointestinal effects. New to the United States, tramadol HCl, which has been prescribed for almost 2 decades in Europe, is a single-entity, centrally acting analgesic that is effective for the management of moderate to moderately severe pain. Although the mechanism of action of this analgesic is not completely understood, animal models suggest that at least two complementary modes of action appear applicable: (1) binding of parent compound and mono-O-desmethyltramadol (M1 metabolite) to the mu-opioid receptor and (2) weak inhibition of norepinephrine and serotonin reuptake. Clinical experience suggests that tramadol appears to have a low potential for abuse or addiction. Results from clinical trials conducted in the United States as well as European postmarketing surveillance studies indicate that tramadol is an effective analgesic that may have a particularly important role in the management of chronic painful conditions.
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PMID:Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl. 876 60

This study was performed to examine some ocular actions of an opioid agonist. Experiments were performed to evaluate the effects of a delta opioid agonist, DPDPE ([D-pen2, D-pen5]enkephalin (where pen = penicillamine)), on: 1) intraocular pressure (IOP) in rabbits; 2) cAMP accumulation in rabbit iris ciliary bodies (ICBs). Unilateral, topical administration of DPDPE caused bilateral depression of IOP. Intravitreal injection of DPDPE caused a greater IOP decrease than intravitreal injection of NaH2PO4 (vehicle). Topical administration of naloxone partially inhibited the effect of DPDPE on IOP in normal rabbits. In other experiments, DPDPE suppressed both basal and isoproterenol (ISO)-stimulated cAMP accumulation in ICBs. The presence of naltrindole (NTI), a delta receptor antagonist, did not prevent the suppression of cAMP levels by DPDPE. The conclusions drawn from the findings suggest that the lowering of IOP by DPDPE is mediated, in part, by actions at postjunctional (ciliary body) sites and may involve an atypical opioid receptor.
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PMID:Ocular action of an opioid peptide, DPDPE. 877 29

The effects of substance P (SP) and the naturally occurring met-enkephalin and the synthetic mu-specific opioid agonist, DAGO (Tyr-D-Ala-Gly-N-Methy-Phe-Gly-ol) and the delta-specific opioid agonist DADL (Tyr-D-Ala-Gly-Phe-D-Leu) on basal ventilation were investigated in halothane-anaesthetized rats. Local injections of SP (0.75-1.5 nmol) in the ventrolateral medulla oblongata (VLM), e.g. nucleus paragigantocellularis, and nucleus reticularis lateralis increased ventilation because of an elevation of tidal volume. Met-enkephalin induced a short-lasting ventilatory depression mainly because of a depression of tidal volume. Activation of delta- and mu-opioid receptors in the VLM by local application of DADL and DAGO, respectively, induced ventilatory depression, which was later in onset and more long-lasting. Local administration of met-enkephalin into the VLM also produced a long-lasting inhibition of the SP-induced ventilatory excitation. A similar blockade of the SP-induced excitatory ventilatory response could be elicited by DADL but not by DAGO. This antagonistic effect was attenuated by local application of the delta-opioid receptor antagonist ICI 154. 129. We conclude that the naturally occurring met-enkephalin as well as synthetic mu- and delta-specific enkephalin analogues (DAGO and DADL, respectively) in VLM depress basal ventilation by an effect on inspiratory drive. There is a functional antagonism between activation of delta-opioid receptors and SP receptors into the VLM in respect to respiratory regulation.
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PMID:Substance P-induced respiratory excitation is blunted by delta-receptor specific opioids in the rat medulla oblongata. 880 Mar 56

Effect of nitrous oxide (N2O) on the somatosympathetic A- and C-reflexes was investigated using artificially ventilated rats anesthetized with alpha-chloralose and urethane. Somatocardiac sympathetic A- and C-reflexes were elicited in the inferior cardiac nerve by electrical stimulation of A and C afferent fibers of the tibial nerve, respectively. Both reflexes were depressed by inhalation of N2O for 20 min. The depression was greater in the C-reflex than in the A-reflex. The depressive effects of N2O on both reflexes were unchanged after pretreatment with intravenous naloxone (0.2 or 2.0 mg/kg) or by prolongation of the inhalation of N2O for 2 h. These results suggest that the opioid receptor is not involved and that acute tolerance is not developed in the depressive action of N2O on the somatosympathetic A- and C-reflexes.
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PMID:Nitrous oxide depresses somatocardiac sympathetic A- and C-reflexes in anesthetized rats. 884 12


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