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)

In an effort to evaluate the feasibility of kappa-opioid receptor agonists for use in pregnancy, we have investigated the actions of U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide) on cardiovascular and respiratory control in the unanaesthetized ovine foetus. Intravenous administration of U50,488H (1.0 mg/kg) to the foetus resulted in an immediate increase in foetal blood pressure (P < 0.0001) and heart rate (P < 0.0001) which lasted 15 min, followed by a prolonged loss of heart rate variability for up to 3 h. There was also a significant suppression of foetal breathing movements for 2-3 h (P < 0.008). Pretreatment with naloxone (12 mg/h) completely blocked the hypertensive and tachycardiac response to U50,488H, but was unable to prevent the loss of variation in heart rate or respiratory depression. These data suggest that U50,488H can exert direct cardiovascular and respiratory actions in the ovine foetus via both opioid and non-opioid mechanisms. The naloxone-insensitive suppression of foetal breathing would severely limit the use of U50,488H as an obstetrical analgesic.
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PMID:Cardiovascular and respiratory actions of U50,488H in the unanaesthetized ovine foetus. 885 Nov 69

The mu-opioid receptor antagonist effects of naloxonazine on levorphanol-induced thermal antinociception and respiratory depression were examined in rhesus monkeys. Levorphanol (0.032-3.2 mg/kg) produced dose-dependent increases in tail-withdrawal latencies from 50 degrees C water in a warm-water tail-withdrawal assay and dose-dependent decreases in ventilation in both air and 5% CO2 mixed in air. Naloxonazine (0.1-3.0 mg/kg) antagonized both the antinociceptive and ventilatory effects of levorphanol to a similar degree, and the antagonist effects of naloxonazine were greater after 1 h than after 24 h. Under all conditions, the antagonist effects of naloxonazine were fully surmountable. Schild analysis of the antagonist effects of naloxonazine after 1 h pretreatment in the antinociception assay yielded a pA2 value of 7.6 and a slope of -0.50; by comparison, quadazocine yielded a pA2 value of 7.5 and a slope of -1.05. These results suggest that naloxonazine acts as a potent and fully reversible mu-opioid receptor antagonist with a moderately long duration of action in rhesus monkeys. In addition, these results suggest that the antinociceptive and ventilatory effects of mu-opioid receptor agonists in rhesus monkeys are mediated by pharmacologically similar populations of mu opioid receptors.
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PMID:Naloxonazine antagonism of levorphanol-induced antinociception and respiratory depression in rhesus monkeys. 886 16

Several fentanyl analogs (Bagley et al., 1989, J. Med. Chem. 32, 663) were compared to fentanyl and morphine for their effects on respiratory depression as determined by arterial blood gas (pH, pCO2 and pO2) measurements. Fentanyl (0.1 mg/kg), morphine (10 mg/kg), #16 (1-phenethyl-4-[N-(pyridin-2-yl)-N-(methoxymethylcarbonyl)amino] piperidine, 1 mg/kg), #17 (1-phenethyl-4-[N-(pyridin-2-yl) -N-(2-furoyl)amino]piperidine, 0.5 mg/kg) and #29 (1-phenethyl-4-[N- (pyrimidin-2-yl)-N-(methoxy-methylcarbonyl) amino]piperidine, 10 mg/kg) produced significant respiratory depression in rats. Pretreatment with the mu1-opioid receptor selective antagonist, naloxonazine (10 mg/kg), blocked the respiratory effect of fentanyl and its analogs, but not that of morphine. The results suggest that the mu1-opioid receptor plays an important role in the respiratory effects of fentanyl and its analogs. Hence, the mechanism of fentanyl-induced respiratory depression appears to be distinct from that produced by morphine. The most likely explanation for this difference is the possible contribution of muscle rigidity and catalepsy to the observed changes in blood gas parameters caused by the fentanyl analogs, while the respiratory depression of morphine, measured by these same parameters, appears to be independent of its effect on muscle rigidity.
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PMID:Evidence for mu1-opioid receptor involvement in fentanyl-mediated respiratory depression. 889 2

Tramadol is a centrally acting analgesic that has been shown to be effective in a variety of acute and chronic pain states. Unlike other centrally acting analgesics, it exerts a dual action by binding to the opioid receptor site in the central nervous system and by weakly inhibiting the reuptake of biogenic amines. Tramadol is rapidly and almost completely absorbed, with an onset of action occurring within 1 hour of oral administration. The recommended dosage is 50 to 100 mg every 4 to 6 hours; however, regular administration is an alternative, particularly for chronic pain states such as osteoarthritis, where the use of the recently developed sustained release formulation may represent an important advantage. Published studies specifically evaluating the use of tramadol in this disease support its effectiveness. Nausea, drowsiness, constipation, dizziness, and sweating have been reported in association with tramadol use. Nausea occurs early in the course of administration, and may be reduced by slowly titrating the dose of tramadol against response. Tramadol would appear to be particularly useful in the elderly population affected by osteoarthritis because, unlike nonsteroidal anti-inflammatory drugs, it does not aggravate hypertension or congestive heart failure, nor does it have the potential to cause peptic ulcer disease. Compared with narcotics, tramadol does not induce significant respiratory depression, constipation, or have significant abuse potential.
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PMID:Pharmacology and clinical experience with tramadol in osteoarthritis. 891 98

1. Single pulse electrical field stimulation (EFS, 0.5 ms pulse width, 60 V at a frequency of 0.05 Hz) induced twitch contractions of mucosa-free circular muscle strips from the guinea-pig proximal colon which were abolished by atropine (0.3 microM), tetrodotoxin (0.3 microM) or omega-conotoxin GVIA (0.1 microM). 2. Various opioid receptor agonist concentration-dependently inhibited twitches with the following rank order of potency (EC50 values in brackets): U 50488 (0.31 nM) > dermorphin (4.3 nM) = dynorphin A (1-13) (6.2 nM) > [D-Ala2, N-MePhe4, Gly5-ol]-enkephalin (DAMGO, 33.5 nM) = [D-Ala2, D-Leu5]-enkephalin (DADLE, 60 nM) > [D-Pen2, D-Pen2, D-Pen5]-enkepahlin (DPDPE, 1144 nM). 3. Peptidase inhibitors (captopril, thiorphan and bestatin, 1 microM each) did not modify the amplitude of twitches. In the presence of peptidase inhibitors the concentration-response curve to dynorphin A (1-13) was displaced to the left to yield an EC50 of 0.35 nM, comparable to that of the selective kappa receptor agonist, U50488. The curves to the other opioid receptor agonist were unaffected by peptidase inhibitors. 4. DPDPE, DADLE, dermorphin and DAMGO consistently induced a concentration-unrelated transient increase in basal tone and a small and transient facilitation of twitches before development of their inhibitory effect. These transient excitatory effects were not observed upon application of dynorphin A (1-13) or U 50488. The contraction produced by DPDPE (30 nM) was largely inhibited (> 80%) by 1 microM atropine. 5. Twitches suppression induced by dynorphin A (1-13) (30 nM) was partly reversed (46 +/- 8%, n = 6) by naloxone (0.3 microM). The potent and selective kappa opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 3-100 nM)) did not affect the amplitude of twitches and potently antagonized (pKB 9.83 +/- 0.09, n = 10) the inhibitory effect of dynorphin. 6. Naloxone (1-300 nM) concentration-dependently depressed the cholinergic twitches: this depressant effect was largely counteracted in the presence of apamin (0.1 microM) and NG-nitro-L-arginine (30 microM) which potentiated cholinergic twitches on their own. 7. Dynorphin A (1-13) (10 nM, n = 6) did not affect the contractile response to exogenous acetylcholine (1 microM), indicating that depression of evoked twitches occurs prejunctionally. 8. We conclude that multiple opioid receptors modulate cholinergic twitches in the circular muscle of guinea-pig proximal colon. While mu and delta opioid receptor agonists produced mixed excitatory and inhibitory effects, kappa opioid receptors, activated by sub-nanomolar concentrations of dynorphin A (1-13), mediate a powerful and pure prejunctional inhibition of acetylcholine release.
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PMID:Role of kappa opioid receptors in modulating cholinergic twitches in the circular muscle of guinea-pig colon. 892 49

Whole-cell voltage-clamp recording was used to examine the effects of mu-opioid receptor agonists DAGO (Tyr-D-Ala-Gly-MePhe-Gly-ol-enkephalin) and PL017 (Tyr-Pro-N-MePhe-D-Pro-NH2) on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced currents in acutely isolated spinal dorsal horn (DH) neurons from laminae I-IV of young rats. We found that the peak and steady-state amplitude of the AMPA-induced current were depressed by mu-opioid agonists (1 nM-5 microM) in a dose-dependent manner in about 80% of the tested cells. When experiments were performed using whole-cell perforated patch technique, similar depression of AMPA current was produced by mu-opioids. The mu-opioid receptor selective antagonist CTAP (100 nM) prevented or reduced the depressant effects of DAGO and PL017. Intracellular dialysis with guanosine 5'-O-(2-thiodiphosphate) (GDP-beta-S, 0.2 mM) significantly diminished the PL017-induced depression of AMPA responses. In addition, when the cells were dialyzed with guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S, 0.1 mM) the amplitude and duration of the PL017-induced depression was significantly enhanced. Besides depressing the AMPA responses of DH cells, co-application of PL017 and kainic acid (KA) decreased the magnitude of the KA-induced current in 60% of the tested cells. These results indicate that in acutely isolated rat DH neurons, the activation of mu-opioid receptor inhibits AMPA-activated current through activation of a G-protein. This action may contribute to the regulation of the strength of the primary afferent neurotransmission including nociception.
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PMID:mu-Opioid receptor-mediated reduction of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-activated current in dorsal horn neurons. 892 96

Opioids decrease the sympathetic and somatic responses to noxious stimulation and can be given in high doses without negative inotropic effects, even in patients with impaired cardiac function. With currently available opioids, precise titration of dose to effect is difficult, and high doses result in drug accumulation and prolonged respiratory depression. Remifentanil is a new synthetic opioid with direct action on mu-opioid receptors. It has a rapid onset and short latency to peak effect. It is rapidly inactivated by esterases in both blood and tissues, resulting in a very short duration of action. The context-sensitive half-life remains very short (3 to 4 minutes), independent of the duration of infusion. These characteristics facilitate titration of dose to effect and also allow the use of very high doses (ED99) without prolonging recovery from its effects. The duration of action of remifentanil has been found to be short, even in patients with renal or hepatic failure, although only low doses have been used in the studies published to date. The hydrolysis of remifentanil produces a metabolite with very weak opioid receptor activity that does not contribute to the effects of remifentanil. Possible disadvantages of the drug include (1) the need to mix the lyophilized drug with a diluent, (2) administration as a continuous infusion, (3) risk of rapid loss of analgesic and anesthetic effects if the infusion is interrupted accidentally, and (4) difficulty in judging the dose of another, longer lasting opioid that will be required to control postoperative pain without producing excessive ventilatory depression. Remifentanil is likely to be more expensive than other opioids, but its use may reduce overall costs if prompt recovery from its effects results in shorter stays in the operating room and recovery units.
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PMID:The pharmacokinetics of remifentanil. 898

Morphine is a potent opioid analgesic widely used for the treatment of acute pain and for long-term treatment of severe pain. Morphine is a member of the morphinan-framed alkaloids, which are present in the poppy plant. The drug is soluble in water, but its solubility in lipids is poor. In man, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may also take place in the brain and the kidneys. The glucuronides are mainly eliminated via bile and urine. Glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier. Although morphine glucuronidation has been demonstrated in human brain tissue, the capacity is very low compared to that of the liver, indicating that the M3G and M6G concentrations observed in the cerebrospinal fluid (CSF) after systemic administration reflect hepatic metabolism of morphine and that the morphine glucuronides, despite their high polarity, can penetrate into the brain. Like morphine, M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear to compete for opioid receptor binding. The analgesic properties of M6G were recognised in the early 1970s and more recent work suggests that M6G might significantly contribute to the opioid analgesia after administration of morphine. The analgesic potency of M6G after intracerebroventricular (ICV) or intrathecal (IT) administration in rats is from 45-800 timer greater than that of morphine, depending on the animal species and the experimental antinociceptive test used. Furthermore, the development of a sensitive high-performance liquid chromatography (HPLC) assay for the quantitative determination of morphine, M6G and M3G has revealed that M6G and M3G were present in abundance after chronic oral morphine administration and that the area under the plasma concentration-time curve exceeded that of morphine. M3G has been found to antagonise morphine and M6G induced analgesia and ventilatory depression in the rat, which has led to the hypothesis that M3G may influence the development of morphine tolerance. M3G exhibits no analgesic effect after ICV or IT administration. Some studies do, however, indicate that M3G may cause non-opioid mediated hyperalgesia/allodynia and convulsions after IT administration in rats. These observations led to the hypothesis that M3G might be responsible for side-effects, hyperalgesia/allodynia and myoclonus seen after high-dose morphine treatment.
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PMID:Morphine metabolites. 906 Oct 94

The objective of the experiments was to investigate the cellular basis of the inotropic effect on myocardium of several opioids which have been implicated in producing cardiotoxic effects in human poisoning. Opioids exerted negative inotropic effects, with half-maximal concentrations between 10 microM (dextropropoxyphene) and 118 microM (pethidine); all agents reduced the magnitude of the intracellular Ca2+ transient and the L-type Ca2+ current, ICa, over a similar concentration range to that which reduced twitch tension. The depression of ICa correlated positively with the value of the opioid oil-water partition coefficient. Effects were not antagonized by the opioid receptor antagonist naloxone. Action potential upstroke rate was also reduced but at significantly higher concentrations. Resting potential and action potential duration were not consistently affected; none of the opioids tested altered intracellular pH. These data suggest that opioids exert a negative inotropic effect by their action on ICa; blockade of the Na+ current is not great enough to exert a significant action. The lack of effect of naloxone implies the actions are independent of the opioid receptor. The correlation of effects with the oil water partition coefficient implies a non-specific effect dependent on the hydrophobicity of the agent.
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PMID:The mode of action of several opioids on cardiac muscle. 912 40

The arcuate nucleus of the hypothalamus, a highly sexually dimorphic brain region, has been called the bed nucleus for endogenous opioids. The potential contribution of opioids in this nucleus to modulate control of ventilation in male and female rats has not been investigated. The purpose of the present study is to determine the effect of microinjecting naloxone, an opioid receptor antagonist, into the arcuate nucleus of awake male and female rats on ventilation, oxygen consumption, heart rate, and blood pressure. Results of this study demonstrate that naloxone at doses of 1.5 and 3.0 nmol relative to vehicle caused a depression of ventilation due to a decrease of both frequency of breathing and tidal volume in male rats and a decreased response to a hypercapnic challenge in female rats. Although there were gender differences noted in oxygen consumption, heart rate, blood pressure, and ventilatory response to a hypoxic challenge, only oxygen consumption was significantly affected by naloxone. Potential mechanisms whereby naloxone may act to depressing ventilation are discussed.
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PMID:Naloxone microinjected into the arcuate nucleus has differential effects on ventilation in male and female rats. 927 60


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