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There are increasing numbers of reports on the tobacco smoking and ingestion of abused drugs (e.g. morphine, cocaine) by pregnant women and the effects of the substances on the developing fetus and newborn infant. The passage of drugs and chemicals from the mother to the fetus is influenced by the placental transport and metabolism of the substances. Further, these drugs and chemicals affect the nutrient transport systems in the placenta. The three major drugs of abuse-nicotine, morphine and cocaine-depress both active amino-acid uptake by human placental villi and transplacental amino-acid transport by reason of the drugs' influence on placental cholinergic and opiate systems. Part of this depression (10-16%) is not reversible. Nicotine blocks the cholinergic receptor and thus blocks acetylcholine (ACh)-facilitated amino-acid transport. Morphine stimulates opiate kappa receptors and depresses ACh release. Cocaine blocks Ca2+ influx and thus blocks ACh release. ACh causes dilation of blood vessels and maintains placental blood flow by the activation of endothelial muscarinic receptors. By interfering with ACh release and placental blood flow, the three drugs of abuse may depress the diffusion of amino acids and other nutrients from the trophoblast into the placental circulation. Three regulatory systems are delineated for amino-acid uptake by the placenta: placental ACh, phospholipid N-methyltransferase, and the gammaglutamyl cycle. These systems operate in concert with one another and are dependent on cellular formation of adenosine 5'-triphosphate (ATP). Placental hypoxia induced by carbon monoxide and other tobacco gases depresses the energy-dependent processes and thus the ATP levels of placental cells. Maternal tobacco smoking and drug abuse cause placental insufficiencies for amino-acid transport, which may partially explain the fetal intrauterine growth retardation caused by these substances. Part of the amino-acid deficits may be compensated for by the induction of new amino-acid transport systems. Specific receptors or drug-binding proteins for the three drugs of abuse are present in the placenta. A DNA adduct selective for maternal smoking has been demonstrated in the placenta. DNA adducts selective for cocaine, morphine and other environmental chemicals have yet to be demonstrated ins the placenta.
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PMID:Placental toxicology: tobacco smoke, abused drugs, multiple chemical interactions, and placental function. 195 23

Morphine, meperidine and ketobemidone used in continuous i.v. infusion for postoperative pain relief were compared in a double-blind, controlled, prospective study in 81 consecutive consenting adult patients after open-heart surgery, with permission from the hospital ethics committee. During the first postoperative period, the infusion rates were fixed. Later on, when the infusion rate could be regulated according to individual patient needs, the variation in infusion rate was large, in accordance with earlier studies. No significant differences were demonstrated between the three analgesics with respect to efficacy of analgesia or side effects like shivering, nausea or vomiting. Respiratory depression following extubation was not observed. During shivering, there was a significant increase in the arterio-mixed venous difference of oxygen in all groups. The amounts of opioids used were relatively small compared to amounts used in patients following abdominal surgery. When interviewed some days after surgery, 18/74 patients remembered moderate pain and 11 severe pain during the stay in the ICU.
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PMID:A comparison between morphine, meperidine and ketobemidone in continuous intravenous infusion for postoperative relief. 200 97

Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were given intracerebroventricularly (i.c.v.) to rats. The antinociceptive effects were assessed in the tail-flick and hot-plate tests as well as the writhing test. Ventilatory effects were studied in halothane-anaesthetized rats. Based on calculated ED50 values, morphine-6-glucuronide was approximately 200 times more potent that morphine itself in the tail-flick and hot-plate tests. In the writhing test the difference in ED50 was approximately 9-fold. Morphine and morphine-6-glucuronide administered i.c.v. induced dose-related decreases in minute ventilation in the dose range 2.7 x 10(-9)-1.3 x 10(-7) mol. The dose-response curve for minute ventilation was steeper for morphine-6-glucuronide than for morphine. Morphine-6-glucuronide was approximately 10 times more potent than morphine in depressing minute ventilation. Morphine-6-glucuronide reduced both tidal volume and respiratory frequency, while morphine reduced only the tidal volume. Morphine-3-glucuronide, in contrast, increased both tidal volume and respiratory frequency, causing an increase in minute ventilation. Apnoea was elicited after the highest doses of morphine-6-glucuronide but not of morphine. The potency difference for depression of minute ventilation between morphine-6-glucuronide and morphine corresponded well to the difference in the writhing test but not to the potency difference in the tail-flick or hot-plate tests. The ventilatory depression induced by morphine and morphine-6-glucuronide was readily reversed by naloxone, while the hyperventilation caused by morphine-3-glucuronide was slightly potentiated by the opioid antagonist. Naloxone pretreatment completely blocked the ventilatory depression induced by morphine-6-glucuronide. These results show that the potent ventilatory depression induced by morphine-6-glucuronide is related to its antinociceptive effects in rats. Furthermore, the fact that morphine-3-glucuronide stimulated ventilation and that morphine had a more shallow ventilatory dose-response curve compared to morphine-6-glucuronide may indicate that morphine-3-glucuronide is a functional antagonist of the depressive effects of morphine and morphine-6-glucuronide on ventilation.
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PMID:Antinociceptive and ventilatory effects of the morphine metabolites: morphine-6-glucuronide and morphine-3-glucuronide. 205 Jan 92

Preliminary research demonstrated that formalin injected into the foot of leghorn cockerels elicited significantly more footlifts of longer duration than physiological saline. The formalin test was subsequently used to examine morphine effects in this species. Previous research demonstrated strain-dependent naloxone-reversible morphine hyperalgesia against thermal nociception in cockerels. In Experiment 1 herein White Leghorn cockerels were given either 0.0, 0.5, 1.5, or 2.5% formalin SC into the foot 30 min after an IM injection of either physiological saline or 2.5 mg/kg morphine sulfate. The frequency and duration of formalin-elicited footlifts increased significantly as a function of formalin concentration. Morphine significantly increased footlift frequency and duration at all but the 0.0% formalin concentration. Morphine inhibited respiration in these animals. In Experiment 2, naloxone (5.0 mg/kg) significantly reversed both the hyperalgesia and the respiratory depression induced by morphine. These results demonstrate that morphine hyperalgesia in leghorn cockerels is neither unique to hot plate test procedures nor peculiar to thermal nociception. Atypical morphine effects in this model may be specific to nociception, however, because hyperalgesia was not accompanied by atypical morphine effects on respiration.
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PMID:Morphine hyperalgesic effects on the formalin test in domestic fowl (Gallus gallus). 205 96

Morphine (0.5-4 mg/kg, iv) caused dose-dependent decreases of respiratory frequency (FR), minute volume (Vm) and PaO2 and an increase of PaCO2 in rabbits. These effects of morphine were reversed by pilocarpine (2.5 mg/kg, icv) .4-Amino pyridine (4-AP, 1.5 micrograms/kg, icv) caused increase of FR and PaO2 and reduction of PaCO2 with marked increase in Vm. When 4-AP was administered in combination with different doses of morphine, the respiratory depressant effect was reduced and the dose-effect curve was shifted to the right. Following administration of reserpine (1 mg/kg, iv) which depleted the brain of its catecholamine content, morphine (4 mg/kg, iv) was still capable of decreasing FR and Vm, and 4-AP could abolish this effect completely. Morphine (4 mg/kg) caused the most dramatic reduction of Ach contents in pons and medulla oblongata in rabbits 30 min after administration, and remained so until 60 min. Varying the dose of morphine (2-8 mg/kg) caused dose-dependent reduction of Ach contents in the above mentioned brain areas. The time course and dose-effect of respiratory depression showed a close correlation with those of the decline of Ach contents in lower brain stem (r = 0.9301, P less than 0.01). The results showed that the respiratory depression by morphine was related to the reduction of Ach contents in lower brain stem and hence causing decrease of Ach release.
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PMID:[Relationship between morphine-induced respiratory depression and the cholinergic system of respiratory center]. 208 78

The effect of i.v. morphine on the spinal nociceptive flexor reflex was examined in decerebrate, unanesthetized rats in which the spinal cord was acutely or chronically transected. In acutely spinalized rats i.v. morphine dose dependently depressed the flexor reflex with an ED50 of 1.4 mg/kg. In rats in which the spinal cord was transected 1-3 days prior to the electrophysiological experiments, i.v. morphine had a similar depressive effect (ED50 = 1.1 mg/kg). However, 4-6 days after spinalization there was a 4-fold increase in morphine's depressive effect (ED50 = 0.35 mg/kg). The sensitivity to morphine was further increased 7-10 days post-spinalization with ED50 of 0.17 mg/kg. This supersensitivity was maintained up to 30-60 days. The reflex depression caused by morphine in both acutely and chronically spinalized rats could be reversed by naloxone. Morphine i.v. did not influence the monosynaptic reflex in either acutely or chronically spinalized rats. The present results support the clinical finding that patients with spinal lesions have an increased sensitivity to the antinociceptive and reflex depressive effects of systemic and intrathecal morphine.
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PMID:Depression of the flexor reflex by systemic morphine increases in chronically spinalized rats. 208 50

Acute administration of naloxone to preweanling rats does not attenuate independent ingestion of milk until 14 days of age suggesting that the full expression of an endogenous opioid system(s), regulating feeding rats, is not complete prior to this age. The present study was undertaken to examine the functional ontogeny of opioid receptors mediating opiate-induced feeding in rats. Rat pups, satiated with milk, were given intraperitoneal injections of the opiate receptor agonist, morphine, and were allowed free access to milk. Morphine stimulated the intake of milk at 3, 5, 7, 14 and 21 days of age, within 2 hr of injection. A time-course analysis in 7-day-old pups showed greater enhancement of intake between hours 2 and 4, than between hours 0 and 2, for large doses of morphine (0.3 and 1.0 mg/kg) suggesting that morphine-induced behavioral depression, which was observed early in the test session, confounded intake at earlier hours. Administration of the opiate receptor antagonist, naltrexone, produced no effect on intake of its own, but blocked the stimulation of intake by morphine in 5-day-old pups confirming that the effect of morphine on the intake of milk was mediated by opioid receptors. Thus, while a functional endogenous opioid system(s), regulating feeding in rats, is not fully mature until 14 days postpartum, the present results suggest that opioid receptors mediating feeding are functional very early in the postnatal development of the rat.
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PMID:The ontogeny of opioid receptors mediating opiate-induced feeding in rats. 216 94

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

Morphine slows hepatobiliary elimination of sulfobromophthalein in rodents, raising dye levels in plasma and liver. Earlier studies showed these effects to be independent of other opiate effects such as bile duct spasm, hypothermia or blood gas changes resulting from respiratory depression. Because opiate receptors are distributed throughout the body, within the central nervous system and at peripheral sites including the gastrointestinal tract, experiments were performed to ascertain whether central or peripheral sites mediate the hepatobiliary effects of morphine. Sulfobromophthalein was administered intravenously to mice and its levels were measured in plasma and liver. Tail-flick latency indicated centrally mediated analgesia. Inhibited intestinal transit of India ink reflected an opiate effect with a significant peripheral component. When injected into a cerebral ventricle morphine was much more potent in producing analgesia and raising sulfobromophthalein levels than when administered intravenously or intraperitoneally. An intravenous dose of naloxone that reversed morphine analgesia also prevented sulfobromophthalein elevation but did not prevent gut slowing. Naltrexone injected in a cerebral ventricle also reversed analgesia and sulfobromophthalein elevation but not intestinal slowing. The polar opiate agonist N-methylmorphine did not cause analgesia or raise sulfobromophthalein levels at peripheral intraperitoneal doses to 100 mg/kg. When given in a central ventricle at 4 x 10(-3) mg/kg, this agent produced analgesia and raised sulfobromophthalein but did not slow intestinal transit. After spinal cord transection, intravenous morphine did not retard the tail-flick response or affect sulfobromophthalein disposition, but peripherally mediated intestinal transit was slowed as it was in intact mice. These experiments demonstrate parallel opiate effects on analgesia and on BSP disposition but not on intestinal transit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hepatobiliary effects of morphine are mediated in the brain. 217 93

1. A 43-year-old male developed acute kidney failure due to ethylene glycol poisoning. He was treated with bicarbonate to combat metabolic acidosis, ethanol as an antimetabolite and haemodialysis to remove the glycol and its toxic metabolites. He was kept on a respirator and sedated with morphine. Peritoneal dialysis was given for 36 d. Following sedation with morphine for 11 d, the patient was given naloxone and then extubated. The antidote had to be continued for 14 d to prevent respiratory depression, until kidney function improved. 2. Only morphine-6-glucuronide (M-6-G) was found in the plasma and CSF at concentrations which might explain the opioid effects observed in the patient during the days after the cessation of morphine treatment. The ratio of the area under the concentration-time curve (AUC) of morphine-3-glucuronide (M-3-G) to M-6-G was 2:1. The elimination half-lives of M-3-G and M-6-G were 55 and 82 h, respectively. The clearance data indicate that most of the glucuronides were eliminated by peritoneal dialysis during renal failure. 3. The data suggest that M-6-G exerts opioid effects and is retained in acute kidney failure. Morphine should therefore not be used preferentially as a sedative/analgesic in pronounced kidney failure.
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PMID:Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure. 226 Dec 46


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