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:C0344307 (analgesia)
28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increase in the disposition of naloxone to the mouse brain was observed for animals previously exposed to morphine. Compared to controls, mice receiving morphine sulfate (10 mg/kg, sc) 3 hr prior to naloxone had a 28% increase in naloxone concentration in brain (200 to 260 pmol of naloxone per g of brain) 10 min after 3H-naloxone-HCl (0.4 mg/kg, 11.0 micronCi/kg, sc) administration. Also, if similar morphine-pretreated mice received a second dose of morphine sulfate (1.0 mg/kg, sc) concurrent with 3H-naloxone-HCl, the morphine-induced enhancement of 3H-naloxone concentration in brain was unaltered. This drug-treatment protocol paralleled that used by others in pA2-analgesia assays to demonstrate sensitization to naloxone for morphine-pretreated animals. In prior (3 hr) morphine-treated animals, administration of 3H-naloxone-HCl (0.1 mg/kg, 33.3 micronCi/kg) iv resulted in an 11.0% increase in 3H-naloxone brain concentration after 1 min. Thus, the enhancement of naloxone brain concentration was independent of the route of naloxone administration. No enhancement of 3H-naloxone brain concentration could be seen 24 hr after morphine sulfate pretreatment (10 mg/kg, sc), a decline in the effect similar to that seen for morphine-induced sensitization to naloxone. Finally, when morphine pellet-implanted mice (75 mg of morphine base, 72 hr) were administered 3H-naloxone-HCl (0.4 mg/kg, 10.0 micronCi/kg, sc), only a 22.5% enhancement of 3H-naloxone concentration in brain was obtained, as opposed to a reported 8-fold increase in the potency of naloxone. Thus, although a number of similarities exist between the enhancement by morphine of naloxone concentration in brain and its sensitization to the antagonistic activity of naloxone, a quantitative correlation appears to be lacking between the two phenomena.
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PMID:Enhanced naloxone distribution to the brain by morphine pretreatment in mice. 1 9

After buprenorphine (Bup, 0.8 mg/kg ip) treatment 45Ca-uptake (cpm/mg fresh brain) in vivo by brain slices decreased from 589 +/- 12 and 486 +/- 12 to 522 +/- 14 and 408 +/- 10 and mitochondrial protein bound Tb3+ (Tb3+ relative fluorescent intensity) reduced from 41 +/- 5 and 32 +/- 2 to 30 +/- 3 and 22 +/- 2 in periaqueductal grey and hypothalamus, respectively. A large amount dense precipitate occurred in the myelin sheath and mitochondria in both regions. The 45Ca-uptake evoked by buprenorphine at 16 micrograms/40 microliter in vitro has the similar tendency with that in vivo. Treated by ruthenium red (20 micrograms/mouse ip or icv) before buprenorphine, the above-mentioned effects were all abolished. Similar results were obtained with morphine (Mor, 10 mg/kg ip) and verapamil (Ver, 8 micrograms/mouse icv) instead of buprenorphine and ruthenium red, respectively. These results suggest that Ca2+ transport across neuroplasmic membranes plays a mediator role in drug-induced analgesia.
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PMID:[45Ca-uptake, mitochondrial protein bound Ca2+ and ultrastructural distribution of Ca2+ in some brain regions of mice during drug-induced analgesia]. 170 89

The individual contributions of central (brain) and peripheral (enteric) sites in the mediation of the systemic actions of opioids are not well established. In this study, we made use of naltrexone methobromide, a quaternary analog of naltrexone, to separate the central and peripheral components of the slowing action of morphine on gastrointestinal transit in rats. It was established that i.c.v., but not s.c., administration of quaternary naltrexone antagonized morphine-induced analgesia in the radiant-heat tail-flick assay in rats. Thus, quaternary naltrexone probably does not enter the central nervous system in significant amounts after systemic administration. Systemic quaternary naltrexone antagonized, in a dose-related manner, the delaying effects of morphine on the movement of a charcoal meal along the gastrointestinal tract. Quaternary naltrexone was 30 or 100 times less potent than naltrexone when administered s.c. or i.c.v., respectively. Unlike naltrexone, quaternary naltrexone antagonized morphine-induced slowing of gastrointestinal transit only when administered by the same route (i.e., both s.c. or both i.c.v.). The apparent pA2 for s.c. quaternary naltrexone against s.c. morphine was not significantly different from the apparent pA2 for i.c.v. quaternary naltrexone against i.c.v. morphine. Distinct and independent central and peripheral systems appear to mediate morphine-induced inhibition of gastrointestinal transit in rats. However, the receptors are probably of the same type. Peripherally selective antagonists such as quaternary naltrexone may be useful in reversing morphine-induced inhibition of gastrointestinal transit without affecting analgesia.
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PMID:Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats. 394 2

For various opioid agonists (n = 35) an unsatisfactory correlation between analgesic activity in vivo (mouse) and receptor binding affinity (rat brain) in vitro was obtained. Excellent correlations were observed, however, after separation of the opioid agonists into two groups with mu- and kappa-receptor selectivity, respectively. The correlation of the analgesic potency with the affinity to the opioid kappa-receptor was very high for the group of kappa-agonists, while it was low for the group of mu-agonists. The slopes of the regression lines were near unity and parallel. The shift from the less potent mu-agonists to the more potent kappa-agonists was about one order of magnitude indicating that analgesia of kappa-agonists is mediated by both mu- and kappa-receptors.
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PMID:Differentiation of mu- and kappa-receptors by means of correlation of analgesic potency in vivo and receptor binding affinity in vitro of various opioid agonists. 609 51

We have previously found rat and toad (Bufo marinus) brain to contain inverse ratios of benzomorphan-preferring (kappa/sigma) and morphine-preferring (mu) opioid receptor types. The aim of the present study was to compare in vivo pharmacologic activity of a benzomorphan, ethylketocyclazocine (EKC) and morphine sulfate (MS) in rat and toad. Footshock intensity thresholds for eliciting locomotion were determined and dose-response curves for EKC and MS analgesia were obtained. Drugs were injected subcutaneously. In rats (high mu, low kappa in brain), both compounds produced analgesia and displayed similar sensitivity to naloxone antagonism. The analgesic effects of EKC and MS may, therefore, be mediated by a common receptor type (mu) in this pain test in rats. In toads (high kappa, low mu in brain), MS produced naloxone-reversible analgesia at doses 20-fold higher than were effective in rats. Toads did not display EKC analgesia at doses below those producing motor impairment. Moreover, 50-fold higher doses were required to produce such impairment in toads. Thirty minutes following subcutaneous injection of 3H-EKC, similar concentrations were found in rat and toad brain. Uptake into brain is probably not a factor in the behavioral resistance of toads to EKC.
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PMID:Analgesic effects of ethylketocyclazocine and morphine in rat and toad. 643 31

Nicotinic acetylcholine receptors are members of the ligand-gated ion channel superfamily, that includes also gamma-amino-butiric-acid(A), glycine, and 5-hydroxytryptamine(3) receptors. Functional nicotinic acetylcholine receptors result from the association of five subunits each contributing to the pore lining. The major neuronal nicotinic acetylcholine receptors are heterologous pentamers of alpha4beta2 subunits (brain), or alpha3beta4 subunits (autonomic ganglia). Another class of neuronal receptors that are found both in the central and peripheral nervous system is the homomeric alpha7 receptor. The muscle receptor subtypes comprise of alphabetadeltagamma (embryonal) or alphabetadeltaepsilon (adult) subunits. Although nicotinic acetylcholine receptors are not directly involved in the hypnotic component of anesthesia, it is possible that modulation of central nicotinic transmission by volatile agents contributes to analgesia. The main effect of anesthetic agents on nicotinic acetylcholine receptors is inhibitory. Volatile anesthetics and ketamine are the most potent inhibitors both at alpha4beta2 and alpha3beta4 receptors with clinically relevant IC(50) values. Neuronal nicotinic acetylcholine receptors are more sensitive to anesthetics than their muscle counterparts, with the exception of the alpha7 receptor. Several intravenous anesthetics such as barbiturates, etomidate, and propofol exert also an inhibitory effect on the nicotinic acetylcholine receptors, but only at concentrations higher than those necessary for anesthesia. Usual clinical concentrations of curare cause competitive inhibition of muscle nicotinic acetylcholine receptors while higher concentrations may induce open channel blockade. Neuronal nAChRs like alpha4beta2 and alpha3beta4 are inhibited by atracurium, a curare derivative, but at low concentrations the alpha4beta2 receptor is activated. Inhibition of sympathetic transmission by clinically relevant concentrations of some anesthetic agents is probably one of the factors involved in arterial hypotension during anesthesia.
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PMID:The role of nicotinic acetylcholine receptors in the mechanisms of anesthesia. 1184 19

Target-controlled infusions (TCI) aim to provide constant, user-defined blood concentrations of a drug. The infusion device of such a system is controlled by a microprocessor that uses population pharmacokinetic data and the individual patient's weight and age to continuously calculate the required drug infusion rate to replace losses from the blood compartment due to drug distribution and metabolism. This technology has several exciting applications in anesthesia where stable blood concentrations of drugs are of benefit. TCI of propofol for general anesthesia and sedation are now widely used, but the technology is also being extended to the fields of intra- and postoperative analgesia and to patient-maintained sedation and analgesia. Early work on targeting the effect site (brain) is under way and target-controlled propofol infusions are being used in experimental closed-loop anesthesia systems.
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PMID:Current and future applications of target-controlled infusions. 1297 74

Dopamine has been widely implicated as a mediator of many of the behavioural responses to drugs of abuse. To test the hypothesis that dopamine is an essential mediator of various opiate-induced responses, we administered morphine to mice unable to synthesize dopamine. We found that dopamine-deficient mice are unable to mount a normal locomotor response to morphine, but a small dopamine-independent increase in locomotion remains. Dopamine-deficient mice have a rightward shift in the dose-response curve to morphine on the tail-flick test (a pain sensitivity assay), suggesting either a decreased sensitivity to the analgesic effects of morphine and/or basal hyperalgesia. In contrast, dopamine-deficient mice display a robust conditioned place preference for morphine when given either caffeine or l-dihydroxyphenylalanine (a dopamine precursor that restores dopamine throughout the brain) during the testing phases. Together, these data demonstrate that dopamine is a crucial component of morphine-induced locomotion, dopamine may contribute to morphine analgesia, but that dopamine is not required for morphine-induced reward as measured by conditioned place preference.
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PMID:Morphine reward in dopamine-deficient mice. 1634 Oct 13

The combination of nitrous oxide gas (N(2)O) and isoflurane (ISO) vapor is commonly used in pediatric surgical procedures for human infants and children to produce unconsciousness and analgesia. Because of obvious limitations it is difficult to thoroughly explore the effects of pediatric anesthetic agents on neurons in human infants or children. Due to the complexity of the primate brain, the monkey is often the animal model of choice for developmental neurotoxicology experiments, and it is in the rhesus monkey that the phenomenon of interest (anesthetic-induced neuronal cell death in the brain) has been previously reported. Recent reports indicate that exposure of the developing brain to general anesthetics that block N-methyl-D-aspartate (NMDA)-type glutamate receptors or potentiate gamma-aminobutyric acid (GABA) receptors can trigger widespread apoptotic cell death in rodents. The present study was performed to determine whether prolonged exposure of developing nonhuman primates to a clinically relevant combination of nitrous oxide and isoflurane produces neuronal damage. Postnatal day (PND) 5-6 rhesus monkeys were exposed to N(2)O (70%) or ISO (1.0%) alone, or N(2)O plus ISO for 8 h. Inhalation of the combination of 70% N(2)O+1% ISO produces a surgical plane of anesthesia. Six hours after completion of anesthetic administration the monkeys were examined for neurotoxic effects. No significant neurotoxic effects were observed for the monkeys exposed to N(2)O or ISO alone. However, neuronal damage was apparent when N(2)O was combined with ISO as indicated by increased numbers of caspase-3-, Silver staining- and Fluoro-Jade C-positive cells in the frontal cortex, temporal gyrus and hippocampus. Electron micrographs indicated typical swelling of the cytoplasm and nuclear condensation in the frontal cortex. These data suggest that prolonged exposure to inhaled anesthetics (a combination of N(2)O and ISO) in the developing rhesus monkey results in neuronal damage, and that the cell death observed is apoptotic and necrotic in nature.
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PMID:Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey. 2170 49

Cytochrome P450 2D (CYP2D) mediates the activation and inactivation of several classes of psychoactive drugs, including opioids, which can alter drug response. Tramadol is a synthetic opioid with analgesic activity of its own as well as being metabolically activated by CYP2D to O-desmethyltramadol (ODMST) an opioid receptor agonist. We investigated the impact of brain CYP2D metabolism on central tramadol and ODSMT levels, and resulting analgesic response after oral tramadol administration in rats. CYP2D inhibitors propranolol and propafenone were administered intracerebroventricularly prior to oral tramadol administration and analgesia was measured by tail-flick latency. Drug levels of tramadol and its metabolites, ODSMT and N-desmethyltramadol, were assessed in plasma and in brain by microdialysis using LC-ESI-MS/MS. Inhibiting brain CYP2D with propafenone pretreatment increased analgesia after oral tramadol administration (ANOVA p = 0.02), resulting in a 1.5-fold increase in area under the analgesia-time curve (AUC_0-60, p < 0.01). This effect was associated with changes in the brain levels of tramadol and its metabolites consistent with brain CYP2D inhibition. In conclusion, under oral tramadol dosing pretreatment with a central administration of the CYP2D inhibitor propafenone increased analgesia (without altering plasma drug or metabolite levels), indicating that tramadol itself (and activity of CYP2D within the brain) contributed to analgesia.
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PMID:Centrally administered CYP2D inhibitors increase oral tramadol analgesia in rats. 3292 50


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