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 predominant consequences of mu-opioid-receptor activation are depression of both neuronal activity and transmitter release. Mu-Opioid agonists have previously been observed to increase a potassium conductance and to inhibit adenylate cyclase. We now report that activation of mu-opioid receptors directly decreases the N-type calcium-channel current in a differentiated, human neuroblastoma cell line (SH-SY5Y). The coupling between the mu-opioid receptor and the calcium channel involves a pertussis toxin-sensitive G protein and is independent of changes in adenylate cyclase activity. The inhibition of the calcium-channel current is voltage dependent because it is largely overcome by strong membrane depolarization. It is not associated with changes in the kinetics of current inactivation. Therefore, the mu-receptor belongs to the superfamily of G-protein-coupled, inhibitory neurotransmitter receptors which modulate the activity of calcium and potassium channels and adenylate cyclase.
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PMID:Mu-opioid-receptor-mediated inhibition of the N-type calcium-channel current. 167 47

A series of new 1-(heterocyclyalkyl)-4-(propionanilido)-4-piperidinyl methyl esters and methylene methyl ethers have been synthesized and pharmacologically evaluated. In the mouse hot-plate test, the majority of compounds exhibited an analgesia (ED50 less than 1 mg/kg) superior to that of morphine. These studies revealed a pharmacological accommodation for many more structurally diverse and far bulkier aromatic ring systems than the corresponding components of the arylethyl groups of the prototypic methyl ester (carfentanil, 2) and methylene methyl ether (sufentanil, 3 and alfentanil, 4) 4-propionanilido analgesics. Compound 9A (methyl 1-[2-(1H-pyrazol-1-yl)-ethyl]-4-[(1-oxopropyl)phenylamino]-4- piperidinecarboxylate), which exhibited appreciable mu-opioid receptor affinity, was a more potent and short-acting analgesic, than alfentanil with less respiratory depression in the rat. On the other hand, the phthalimides 57A and 57B, which exhibited negligible affinity for opioid receptors associated with the mediation of nociceptive transmission (i.e., mu-, kappa-, and delta-subtypes), displayed analgesic efficacy in all antinociception tests. In addition, while 57B, compared to clinical opioids, showed a superior recovery of motor coordination after regaining of righting reflex from full anesthetic doses in the rat rotorod test, 57A showed significantly less depression of cardiovascular function at supraanalgesic doses in the isoflurane-anesthetized rat.
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PMID:New 1-(heterocyclylalkyl)-4-(propionanilido)-4-piperidinyl methyl ester and methylene methyl ether analgesics. 184 32

To understand the role of dopamine in the mediation of opiate's analgesic and reinforcing activity, the influence of pharmacologically-induced increase (apomorphine in a high dose) and decrease (haloperidol and apomorphine in a low "presynaptic" dose) of dopamine neurotransmission on morphine-induced depression of vocalization and movement reactivity was investigated in freely behaving rats. Strong enhancement of morphine-induced vocalization reactivity depression and a weakening of movement reactivity depression typical to concomitant pharmacological increase of dopamine neurotransmission may represent the enhancement of its reinforcing and analgesic properties and inhibition of its depressive/sedative activity. Enhancement of MOR-induced depression of movement and vocalization reactivity characteristic of drug-induced decrease of dopamine neurotransmission may be the consequence of the blockade of opiate's reinforcing and stimulatory activity and summation of depressive/sedative actions typical to these drugs administered alone.
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PMID:Dopaminergic involvement in the mediation of morphine effects on vocalization and movement reactivity in the rat. 193 71

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

In summary, these findings indicate the importance of designing future experiments that delineate between opioid and nonopioid forms of respiratory disease and dysfunction, and the need to identify means of diagnosing them in order to achieve successful recovery. Apparently there is great diversity between animal species in terms of contributions of endogenous opioids to tonic control of ventilation, and future work should strive to identify which species is most appropriate as a model of human ventilatory control and disease. Certain opioid receptor types appear to be linked to independent respiratory functions. For instance, mu receptors in the brain stem produce strong inhibitory actions on respiratory parameters, including RR, VT, VE, and CO2 sensitivity. These effects have been observed in vivo and by electrophysiologic recordings in vitro. Delta receptors may also exert some inhibitory effect on respiration, especially in the NTS. In the CNS, the ventral surfaces of the medulla and pons, especially the NTS and NA, seem to be important sites for opioid-induced inhibition of respiration, whereas the spinal cord probably is not involved in opioid-mediated ventilatory depression. Kappa receptors appear to be devoid of respiratory depressant activity, whereas sigma receptors may stimulate some ventilatory parameters. Morphine and similar pure mu agonists, such as fentanyl and oxymorphine, probably produce their analgesic and respiratory depressant effects through stimulation of mu receptors. Mixed agonists/antagonists that have mu antagonist (or partial agonist) activity plus kappa agonist and/or sigma agonist activity show a ceiling effect for respiratory depression. Future tests need to determine which opioid receptor may be responsible for the ceiling effect. In addition, the effects of mu, delta, kappa, and sigma selective agonists on hypoxic drive should also be determined, as a drug that stimulates hypoxic sensitivity in the face of hypercapnic depression may produce less overall respiratory depression due to counteractive effects. In the future, clinically optimal opiates should have more specificity of action than those available now. This may be achieved by creating drugs selective for single receptors or by creating drugs with desirable combinations of receptor selectivities. The combinations of mixed agonists/antagonists with pure mu agonists currently in use today are promising, as they provide analgesia with reduced respiratory depression. In the early days of opiate research and development, combination drug regimens were thoroughly tested to determine the "ideal ratios" that would retain analgesic properties but not the other undesirable effects such as respiratory depression (196).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. 217 88

This paper focuses on the behavioral thermoregulatory effects of i.c.v. administration of [D-Ala2,MePhe4,Gly5-ol]enkephalin (DAMGO), cyclic [D-Pen2,D-Pen5]enkephalin (DPDPE) and U-50,488H, selective agonists for the mu, delta and kappa opioid receptors, respectively. Rats were tested in a thermally graded tunnel (thermocline) which allowed for simultaneous measurement of body temperature, ambient temperature selection and general ambulatory activity levels. DAMGO (0.3 micrograms) caused an increase in body temperature which was facilitated by the selection of a warm ambient temperature. Both DPDPE (30 micrograms) and U-50,488H (100 micrograms) caused decreases in body temperature which were accompanied by a selection of a cool ambient temperature. In each case there was evidence for a regulated change in body temperature, with DAMGO increasing thermoregulatory set point and DPDPE and U-50,488H decreasing set point. DAMGO and U-50,488H produced a depression of activity levels for the first 15 min after injection. DAMGO and DPDPE produced increases in activity levels which peaked after body temperature had returned toward base-line levels. These data characterize further the differentiable profiles of physiological effects produced by these three compounds. The central modulation of the control of body temperature by these opioid receptor agonists may reflect a role of endogenous opioids in thermoregulatory control.
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PMID:Alteration of thermoregulatory set point with opioid agonists. 231 95

During progressive acute cardiac tamponade (CT) in conscious dogs, cardiac output (CO) falls continuously while arterial blood pressure (BP) is well maintained until an abruptly terminal decline. This response is primarily dependent on alpha-adrenergic mechanisms. During hemorrhagic shock, the opioid receptor blocker naloxone increases CO and BP and improves survival perhaps by reversing an opioid-induced cardiovascular depression. We produced 10 episodes of decompensated CT (DCT; 30% decline in BP) by intrapericardial saline infusion (20 ml/min) in five euvolemic conscious dogs. CT resulted in a decrease in CO and BP from base line (3.79 +/- 0.37 l/min and 89.6 +/- 5.2 mmHg, means +/- SE) to DCT (1.35 +/- 0.15 l/min and 57.5 +/- 3.1 mmHg; P less than 0.05). Naloxone (3 mg/kg iv) given at the onset of DCT resulted in a prompt sustained return of BP to base-line levels (P less than 0.05) with no change in CO. Four more animals were studied before and during naloxone (3 mg/kg iv then 0.3 mg.kg-1.min-1 iv). DCT occurred at a higher intrapericardial pressure (20.1 vs. 18.3 mmHg; P less than 0.025) if CT were induced during naloxone treatment than in its absence. Thus naloxone during DCT promptly reversed hypotension with no change in CO and, if present during induction of CT, naloxone allowed slightly higher levels of intrapericardial pressure to be tolerated. Further studies are needed to determine whether naloxone produced these effects solely by its actions on opioid receptors. This study suggests that the interaction between opioid and adrenergic influences plays a role in causing hypotension during CT.
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PMID:Influence of naloxone on response to acute cardiac tamponade in conscious dogs. 238 24

The ability of morphine and other opioid analgesic drugs to diminish hepatocellular glutathione (GSH) concentrations was examined in ICR mice. When administered intraperitoneally, morphine, hydromorphone, ethylmorphine, l-alpha-acetylmethadol (LAAM), and meperidine all caused a significant decrease in hepatic GSH concentrations in male mice while codeine, methadone, butorphanol, nalbuphine, and pentazocine were without effect even at doses up to those approaching acute lethality. Depression of hepatic GSH equivalent to that observed after ip administration could be elicited by icv administration of small doses of morphine, ethylmorphine, and hydromorphone. LAAM and meperidine were ineffective following icv administration in these experiments. The discrepancy between results following ip versus icv administration of LAAM and meperidine suggests that hepatic metabolism of some opioids may be important for their activity in the CNS, as both norLAAM and normeperidine diminished hepatic GSH when administered by the icv route. The opioid-induced lowering of hepatic GSH does not appear to be sex-dependent since morphine and LAAM produced qualitatively and quantitatively similar effects on hepatic GSH in female mice. Morphine administered icv produced a substantial increase in the hepatotoxicity of two compounds dependent upon GSH for detoxification, acetaminophen and cocaine, as measured by serum alanine aminotransferase activities. These observations indicate that a number of opioid analgesic drugs have the potential to diminish hepatic GSH. Further, these results support earlier studies which indicate that central opioid effects on hepatic GSH are mediated through mu-opioid receptor stimulation. Last, these studies suggest that a centrally initiated opioid action on hepatic GSH may significantly influence the susceptibility of the liver to the effects of some hepatotoxic agents.
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PMID:Depression of hepatic glutathione by opioid analgesic drugs in mice. 247 Dec 91

The endogenous opioids and their receptors are known to play a major role in neoplasia. In the present study, naltrexone (NTX), a potent opioid antagonist, was utilized to explore the interactions of opioids and opioid receptors in mice with transplanted neuroblastoma (S20Y). Tumors from mice subjected to either intermittent (4-6h/day; 0.1 mg/kg NTX) or complete (24 h/day; 10 mg/kg NTX) opioid receptor blockade exhibited an up-regulation of DADLE and Met-enkephalin binding sites, as well as tissue levels of beta-endorphin and Met-enkephalin. Binding affinity to [D-Ala2,D-Leu5]enkephalin (DADLE) or ethylketocyclazocine (EKC), the levels of plasma beta-endorphin, and the anatomical location and quantity of Met- and Leu-enkephalin and cytoskeletal components (i.e. tubulin, actin, brain spectrin (240/235) were similar in NTX and control tumor-bearing animals. Tissue viability of the 0.1 NTX group was increased compared to controls. Both mitotic and labeling indexes were increased during the period of opioid receptor blockade, but decreased in the period subsequent to receptor blockade. NTX treatment produced a 2-fold increased in sensitivity to opioids. Met-enkephalin (10 mg/kg) produced a depression in both mitotic and labeling indexes in tumor-bearing mice that could be reversed by naloxone (10 mg/kg) administration. Thus, the endogenous opioids are trophic agents that inhibit growth by suppressing cell proliferation. The duration of receptor blockade by opioid antagonists modulates these actions, affecting both tumor incidence and survival time. Complete opioid receptor block prevents the interaction of increased levels of putative growth-related peptides with a greater number of opioid receptors, thereby increasing cell proliferation and accelerating tumor growth. With intermittent blockade, an enhanced opioid-receptor interaction occurs during the interval when the opioid antagonist is no longer present, producing an exaggerated inhibitory action on cell proliferation and the repression of tumorigenic events.
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PMID:Opioid antagonist modulation of murine neuroblastoma: a profile of cell proliferation and opioid peptides and receptors. 254 Aug 73

A series of studies were conducted in order to further characterize the previously reported effect of morphine to diminish hepatocellular concentrations of glutathione (GSH) in mice. Naive ICR mice administered morphine (i.p.) in doses up to 1000 mg/kg had diminished hepatic GSH concentrations, with a maximum depletion of approximately 50% occurring at doses of 250 mg/kg or greater. No such effect from an acute challenge with morphine was observed in morphine-tolerant mice. The intracerebro-ventricular administration of the opioid receptor antagonist naltrexone (250 micrograms) completely blocked the hepatic GSH depression resulting from the systemic (i.p.) administration of morphine (100 mg/kg). When morphine (100 micrograms) was administered by the i.c.v. route, GSH concentrations in liver and plasma were significantly altered while heart and kidney were unchanged. Variable responses to i.c.v. morphine were obtained in spleen, stomach and lung. The depression of hepatic GSH was found not to be a consequence of morphine-induced hypoxia or hypothermia, and could not be attributed to intracellular oxidation of GSH.
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PMID:Perturbation of glutathione by a central action of morphine. 275 29


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