Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The importance of natural opioids in the central control of blood pressure, heart rate and respiratory function was evaluated with a synthetic analogue of Met-enkephalin, FK 33-824, which is more resistant to enzymatic degradation than the natural opioids. Increasing concentrations (20, 100, 200 and 400 micrograms/ml), perfused through the 4th cerebral ventricle of the conscious dog, induced a concentration-related depression of respiratory function - as reflected in arterial pCO2 and pO2 and heart rate. Naloxone (40 micrograms/ml) was able to reverse respiratory depression whereas bradycardia was naloxone-resistant even after massive (100 micrograms/kg) intravenous doses. Mean arterial blood pressure was not affected in the tested concentration range. Because respiration was reversed by naloxone, it is concluded that respiratory control is regulated by the mu-type opioid receptor. Heart rate, however, may be governed by the delta-type opioid receptor which is less susceptible to naloxone.
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PMID:Perfusion of the fourth cerebral ventricle with the synthetic opioid peptide, FK 33-824, induces dose-related bradycardia and naloxone-reversible respiratory depression in the awake dog. 712 92

In freshly isolated spinal dorsal horn (DH) neurons (laminae I-IV) of the young rat, the effects of dynorphin A1-17, U-50,488H and U-69,593 on inward currents induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) were studied under whole-cell voltage-clamp conditions. When the cells were clamped to a holding potential of -60 mV, co-application of dynorphin A1-17 (10(-6) M) and AMPA (2 x 10(-5) M) reversibly decreased the peak amplitude of the initial transient component of the AMPA-induced current in 72% of the examined cells. In addition, dynorphin (10 microM) in perforated patch-recordings consistently produced a decrease in the steady-state component of the AMPA response. The depressant effect was concentration-dependent (IC50 = 86 nM) and reversible. The dynorphin A1-17-induced depression of the AMPA response was associated with slowing of the response kinetics, including both a 10-90% rise-time and time constant of decay. The AMPA-induced currents were modulated by dynorphin not only during the co-administration but also after the removal of the peptide. Dynorphin increased the initial peak AMPA current in 42% of the examined cells. Similar as with dynorphin A1-17, the peak amplitude of the AMPA-induced current was reversibly suppressed in the presence of 1 microM U-50,488H and U-69,593 in 75% and 86% of the examined cells, respectively. Naloxone and the kappa 1-selective antagonist norbinaltorphimine (nor-BNI) blocked the initial depressant but not late excitatory effects of dynorphin A1-17 and U-50,488H. This antagonistic effect of naloxone and norbinaltorphimine suggests that the depressant effect of dynorphin A1-17 on the AMPA-activated conductance is a true opioid, probably kappa 1-opioid receptor-mediated event. In contrast, the dynorphin-induced late potentiation of AMPA/KA responses appears to be a non-opioid effect since it was not inhibited by nor-BNI, CTAP and naltrindole, the selective kappa-, mu- and delta-opioid receptor blocking agents, respectively. Pretreatment of DH neurons with pertussis toxin blocked the depressant action of dynorphin A1-17, indicating that a Gi- or Go-type G protein was required for this effect on AMPA-activated currents. Intracellular dialysis with a highly specific peptide inhibitor (peptide 6-22) of the cAMP-activated protein kinase (PKA), and with Rp-cAMPS, prevented the depressant effect of dynorphin A1-17. In addition, staurosporine, a nonselective kinase inhibitor, blocked the dynorphin depression of the AMPA response.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The opioid peptide dynorphin modulates AMPA and kainate responses in acutely isolated neurons from the dorsal horn. 753 29

Modulation of somatosympathetic reflexes at the spinal cord and the brainstem was studied by administering opioid receptor agonists into the intrathecal space of the lumbar spinal cord and into the subarachnoid space of the cisterna magna in rats anesthetized with alpha-chloralose and urethane. Somatocardiac sympathetic A- and C-reflexes were elicited by electrical stimulation of myelinated (A) and unmyelinated (C) afferent fibers of the tibial nerve, respectively. Intrathecal administration of the mu-opioid receptor agonist DAMGO selectively depressed the C-reflex in a dose-dependent manner (minimum effective dose 10 ng), whereas the intrathecal injection of the delta-opioid receptor agonist DPDPE and the kappa-opioid receptor agonist U-50,488H only at doses of 10 micrograms and 100 micrograms, respectively, led to a significant depression of the C-reflex. Injection of DAMGO into the cisterna magna enhanced both A- and C-reflexes in a dose-dependent manner (minimum effective dose 1 ng). The administration of neither DPDPE nor U-50,488H into the cisterna magna affected A- or C-reflexes. It is concluded that the activation of mu-opioid receptors is mainly or exclusively responsible for suppressing somatosympathetic C-reflexes at the spinal cord and for enhancing them at the brainstem.
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PMID:Modulation of somatocardiac sympathetic reflexes mediated by opioid receptors at the spinal and brainstem level. 758 6

These studies examined the opioid receptor binding affinities and behavioral effects of several fentanyl derivatives in rhesus monkeys. OHM3295, OHM3296, OHM3326 and OHM3463 displayed high affinity for mu (IC50 = 7-66 nM) as compared to kappa (IC50 = 263-3255 nM) or delta (IC50 = 480-4500 nM) receptors as measured by their ability to displace [3H](D-Ala2-Me-Phe4,Glyol5)enkephalin, [3H](5,7,8[beta])-N-[2- (1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]benzeneacetamide and [3H](D-Pen2-D-Pen5)enkephalin, respectively. All four compounds maintained i.v. self-administration responding at rates above those maintained by the mu agonist alfentanil. In drug discrimination studies, OHM3463, OHM3326 and OHM3296 substituted completely for nalbuphine whereas OHM3295, and a related compound, mirfentanil, substituted partially for nalbuphine. In morphine-treated monkeys, OHM3295 substituted for naltrexone; in monkeys acutely deprived of morphine, only OHM3463 reversed naltrexone-lever responding. All four compounds had antinociceptive effects, although the extent to which these effects were accompanied by respiratory depression or modified by naltrexone, as well as the interactions between antinociceptive effects of fentanyl derivatives and alfentanil, varied markedly among compounds. Thus, OHM3463 shared effects with mu agonists (e.g., alfentanil) under all conditions; the other three compounds had opioid agonist effects under only a subset of conditions. Moreover, one of these compounds (OHM3295) antagonized the discriminative stimulus and antinociceptive effects of other mu agonists. Collectively, these compounds appear to vary on two dimensions: opioid efficacy and the contribution of nonopioid actions to their antinociceptive effects. Together with results obtained with other fentanyl derivatives (mirfentanil) under similar conditions, results of the current study suggest this chemical class might be especially fertile for the development of novel analgesics that might have reduced toxicity and abuse liability as compared to fentanyl and related compounds that are currently used in medicine.
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PMID:Behavioral effects and receptor binding affinities of fentanyl derivatives in rhesus monkeys. 761 95

Whole-cell voltage-clamp technique was used to examine the effects of a mu-opioid receptor agonist DAGO (Tyr-D-Ala-Gly-Me-Phe-Gly-ol-enkephalin) on GABA-induced currents in acutely isolated spinal dorsal horn (DH) neurons from laminae I-IV of young rats. We found that a bicuculline-sensitive GABA-induced current was potentiated by DAGO (0.5-500 nM), in a dose-dependent manner, in approximately 62% of the tested cells. The elevated GABA responses outlasted the period of DAGO application, and either recovered within 10 min after the removal of the peptide or persisted for up to 50 min. The potentiating effect of DAGO was reduced or prevented by naloxone and the mu-opioid receptor-selective antagonist beta-funaltrexamine. A similar enhancing effect on the membrane currents activated by administration of muscimol, a GABAA receptor-specific agonist, was produced by DAGO. In addition, a transient depression of GABA responses was observed in approximately 25% of the cells tested. These results indicate that the mu-opioid agonist DAGO modulates the sensitivity of postsynaptic GABAA receptors in a large proportion of spinal neurons from laminae I-IV, with the major effect being facilitation. The DAGO action could contribute to the regulation of the strength of primary afferent neurotransmission, including nociception.
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PMID:Activation of mu-opioid receptor modulates GABAA receptor-mediated currents in isolated spinal dorsal horn neurons. 770 May 61

We examined interrelationships between theoretically related MMPI-2 and Rorschach variables in a sample of Veterans Affairs outpatients with Posttraumatic Stress Disorder (PTSD). Subjects were 20 White Vietnam combat veterans diagnosed with PTSD who completed the Rorschach and MMPI-2 as part of a comprehensive evaluation. Correlations were calculated for variables in three groups: validity, depression and anxiety, and thought disturbance. Results showed strong relationships between m, MOR, and the Dramatic special score of the Rorschach and MMPI-2 indices of distress. Positive relationships were also found for some indicators of thought disturbance, whereas correlations for other depressive indicators were not significant. Findings are discussed with regard to implications for the clinical assessment of combat-related PTSD and future directions for assessment research.
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PMID:Interrelationship between MMPI-2 and Rorschach variables in a sample of Vietnam veterans with PTSD. 772 56

The granule cell population response to perforant path stimulation decreased significantly within seconds following release of endogenous dynorphin from dentate granule cells. The depression was blocked by the opioid receptor antagonists naloxone and norbinaltorphimine, suggesting that the effect was mediated by dynorphin activation of kappa 1 type opioid receptors. Pharmacological application of dynorphin B in the molecular layer was effective at reducing excitatory synaptic transmission from the perforant path, but application in the hilus had no significant effect. These results suggest that endogenous dynorphin peptides may be released from a local source within the dentate molecular layer. By light microscopy, dynorphin-like immunoreactivity (dynorphin-LI) was primarily found in granule cell axons in the hilus and stratum lucidum with only a few scattered fibers evident in the molecular layer. At the extreme ventral pole of the hippocampus, a diffuse band of varicose processes was also seen in the molecular layer, but this band was not present in more dorsal sections similar to those used for the electrophysiological studies. Electron microscopic analysis of the molecular layer midway along the septotemporal axis revealed that dynorphin-LI was present in dense-core vesicles in both spiny dendrites and unmyelinated axons with the majority (74%) of the dynorphin-LI-containing dense-core vesicles found in dendrites. Neuronal processes containing dynorphin-LI were observed throughout the molecular layer. The results suggest that dynorphin release from granule cell processes in the molecular layer regulates excitatory inputs entering the hippocampus from cerebral cortex, thus potentially counteracting such excitation-induced phenomena as epileptogenesis or long-term potentiation.
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PMID:Dynorphin opioids present in dentate granule cells may function as retrograde inhibitory neurotransmitters. 791 18

Dynorphin A (1-17) was applied directly onto the spinal cord of rats during electrophysiologic recording of the dorsal root potential (DRP) and the ventral root potentials (VRPs), i.e., monosynaptic reflex and polysynaptic reflexes. Dynorphin application resulted in a dose-dependent depression of the DRP (ED50, 4.5 nmol) which persisted for 30 to 50 min. This effect was not antagonized by nor-binaltorphimine, a kappa-opioid receptor antagonist. During this depression we observed a potentiation of the VRPs which persisted for 4 to 5 min and preceded depression of the VRPs (ED50, 4.0-4.9 nmol). The depression of the VRPs was antagonized competitively by nor-binaltorphimine, although the potentiation was not. beta-Funaltrexamine, a mu-opioid receptor antagonist, had no influence on dynorphin-induced changes of evoked potentials. These data indicate that dynorphin-induced depression of the VRPs is mediated by kappa-opioid receptor activity, whereas neither potentiation of the VRPs nor depression of the DRP appears to be mediated by an opioid receptor effect.
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PMID:Pharmacological characterization of dynorphin A (1-17)-induced effects on spinal cord-evoked potentials. 791 12

The influence of naloxone (an opioid receptor antagonist) on spinal cord conduction and edema formation as a result of trauma to the cord was investigated in a rat model. The spinal cord injury (SCI) was inflicted in urethane anesthetized animals by a longitudinal incision into the right dorsal horn of the T10-11 segments, about 2 mm deep and 5 mm long. Spinal cord evoked potentials (SCEP) were recorded epidurally from the T9 (rostral) and T12 (caudal) segments after stimulation of the ipsilateral tibial and sural nerves at the ankle. The edema was measured by determining water content of the cord at s h after injury. In rats not given naloxone SCI resulted in an immediate long-lasting depression of the rostral maximal negative peak (MNP) amplitude (about 60%) and a significant increase in the latency of the rostral maximal positive peak (MPP). Pretreatment with naloxone inhibited the immediate post-injury decrease of the rostral MNP and some of the increase of MPP latency. The water content in the traumatized spinal cord was reduced by 3% in naloxone treated animals compared with untreated injured controls. Our results indicate that endogenous opioid peptides participate in changes of spinal cord conduction after trauma and influence edema formation probably via multiple opioid receptors.
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PMID:Naloxone reduces alterations in evoked potentials and edema in trauma to the rat spinal cord. 797 34

Respiratory depression is a limiting factor in the therapeutic use of opioid analgesics. It has been suggested that respiratory depression is mediated by mu rather than kappa receptors and may involve a decrease in central nervous system sensitivity to hypercapnia. This study investigated opioid receptor mechanisms underlying respiratory depression in unanesthetized rhesus monkeys (n = 3) breathing air or 5% CO2 in air into a pressure displacement head plethysmograph. Apparent pA2 analyses of s.c. quadazocine (a mu-selective antagonist) were carried out on the effects of cumulative doses of s.c. bremazocine, ethylketocyclazocine (EKC) and (+/-)-(1-R/S,5-R/S,2 = R/S)-5,9-dimethyl-2'-hydroxy-2- tetrahydrofurfuryl-6,7-benzomorphan (Mr2033) (compounds with kappa agonist effects in other in vivo assays), alfentanil and etonitazene (compounds with mu agonist effects in other in vivo assays). Alfentanil, bremazocine, EKC and Mr2033 were approximately equipotent in causing dose-dependent depression of respiratory minute volume of CO2-stimulated and air respiration, whereas etonitazene was approximately 10-fold more potent than the above compounds. Dose-effect curves for respiratory frequency, tidal volume and respiratory minute volume for all of the agonists except bremazocine were shifted to the right by increasing quadazocine doses. Together with data previously obtained in drug discrimination and analgesia assays, results of the present study demonstrating homogeneous pA2 values for quadazocine with alfentanil, etonitazene, EKC and Mr2033 strongly suggest that the latter two compounds decrease respiratory function in rhesus monkeys by acting on mu receptors.
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PMID:Apparent pA2 analysis on the respiratory depressant effects of alfentanil, etonitazene, ethylketocyclazocine (EKC) and Mr2033 in rhesus monkeys. 809 21


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