Circulating levels of specific members of chromosome 19 microRNA cluster are associated with preeclampsia development.

PURPOSE: To perform serum microRNA expression profiling to identify members of chromosome 19 miRNA cluster involved in preeclampsia development. METHODS: Serum chromosome 19 miRNA cluster microRNA expression profiling was evaluated at 12, 16, and 20 gestational weeks and at the time of preeclampsia diagnosis, in women who developed preeclampsia (WWD-PE; n = 16) and controls (n = 18) using TaqMan low density array plates. RESULTS: A total of 51 chromosome 19 microRNA cluster members were evaluated. The circulating hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, were differentially expressed between groups (P < 0.05). Compared with controls, serum levels of hsa-miR-518f-3p at 20 GW were useful for identifying WWD-Mild-PE (P = 0.035) and WWD-Severe-PE (P = 0.007). CONCLUSIONS: Serum hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, are differentially expressed between WWD-PE and controls and their role in the development of preeclampsia should be investigated further.

Maternal distress and the development of hypertensive disorders of pregnancy.

Despite the implementation of programmes to improve maternal health, maternal and foetal mortality rates still remain high. The presence of maternal distress and its association with the development of pregnancy hypertensive disorders is not well established. The aim of this study was to evaluate the association between maternal distress and the development of hypertensive disorders in pregnancy in a prospective cohort of 321 Mexican women. Symptoms of maternal distressing were evaluated at week 20th of gestation using the General Health Questionnaire. The presence of acute somatic symptoms, social dysfunction, anxiety and insomnia increased the odds of developing a pregnancy hypertensive disorder by 5.1-26.4 times in study population (p values < .05). Our results support the participation of maternal distress in the development of hypertensive disorders of pregnancy. The implementation of effective programmes prioritising risk factors during pregnancy including the presence of maternal distressing factors is recommended. Impact statement What is already known on this subject: Changes in the nervous, endocrine, and immune systems have been observed in pregnant women with distress conditions leading to gestational disorders. What do the results of this study add: The presence of acute somatic symptoms, social dysfunction, anxiety and insomnia increased the developing of hypertensive disorders in Mexican population. What are the implications of these findings for clinical practice and/or further research: These findings may contribute to a better understanding of the role of the maternal stress in the development of hypertensive disorders of pregnancy, and in the implementation of effective programmes for clinical practice prioritising risk factors during pregnancy, including the presence of maternal distressing factors.

Endogenous opioids are involved in morphine and dipyrone analgesic potentiation in the tail flick test in rats.

The combined administration of low doses of opiates with non-steroidal anti-inflammatory drugs can produce additive or supra-additive analgesic effects while reducing unwanted side effects. We have recently reported that co-administration of morphine with dipyrone (metamizol) produces analgesic potentiation both in naïve and in morphine-tolerant rats. The purpose of this work was to determine the role of opioids on the acute potentiation observed between morphine and dipyrone i.v. in the rat tail flick test. To do this, two experiments were done. In the first one, naloxone was administered 10 min before morphine (3.1 mg/kg), dipyrone (600 mg/kg) or their combination at the same doses. Control animals received saline instead of naloxone. In the second experiment, naloxone (or saline) was given 2 min after reaching the maximal peak effect with each individual analgesic treatment. When naloxone was i.v. administered prior to analgesics, it completely blocked morphine effects, partially prevented morphine/dipyrone antinociception and delayed dipyrone-induced nociception. At 3.1 mg/kg, naloxone produced an increased nociception. When naloxone was given after analgesics, it dose-dependently blocked the effects of morphine alone and in combination with dipyrone but with different potency in each case. As to dipyrone, naloxone delayed the time to antinociceptive peak effect. Taken together, these results support the notion that endogenous opioids are involved in the analgesic potentiation observed with the combination of morphine plus dipyrone.

Mecanismos de tolerancia analgésica a los opioides

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Abstract: Opioid agonists medíate their analgesic effects by interacting with Gi/o protein-coupled receptors. Acute opioid administration produces: a) an inhibition of the adenylate cyclase (AC) pathway; b) an activation of G-coupled inwardly rectifying potassium channels (GIRKs); and c) a blockade of voltage-dependent calcium channels. All these effects result in cell hyperpolarization and neurodepression. In addition, opioids can stimulate the hydrolysis of phosphatidylinositol by activation of phospolipase C with the resulting calcium release from intracellular storages. However, this is a short-lasting excitatory effect. The development of analgesic tolerance to opioids after repeated administration is an undesirable side effect in clinical practice that limits their use for prolonged treatments. This paper reviews the main mechanisms that have been proposed to play a role in the development of opioid-induced analgesic tolerance, as well as the drugs that have some efficacy in reducing or preventing it. Tolerance is a complex process involving several neurotransmitter systems and neural adaptations occurring at different levels. It does not seem to be due to metabolic changes because concentrations of the main morphine metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), are not significantly changed in tolerant patients. There is sound evidence suggesting that the main changes underlying tolerance development are pharmacodynamic in nature. These changes occur at: a) the receptor level; b) the second messenger level; and c) other neurotransmitter systems. At the receptor level, three different processes have been described: 1. phosphorilation-mediated desensitization; 2. (3-arrestin-dependent endocytosis; and 3. receptor down regulation. These processes can affect opioid receptors themselves (homologous changes) and/ or receptors to other neurotransmitters (heterologous changes). Different researchers have pointed out that there are some inconsistencies between the level of agonist-induced receptor endocytosis and the degree of analgesic tolerance produced by opioid agonists. For example, morphine does not promote efficient receptor internalization, but it produces a strong intracellular signal and, after repeated administrations, a high degree of tolerance. The opposite occurs with other opioids such as DAMGO, methadone and some 5-agonists; i.e., they produce low tolerance, but a high degree of receptor endocytosis. This fact has led to the development of a new theory which proposes that opioid-induced compensatory intracellular changes play an important role in tolerance development. These compensatory changes are more difficult to reverse than changes occurring at the receptor level, because receptor sequestration does not necessarily commit receptors to degradation, but lead, at least in part, to dephosphorilation and receptor recycling to the cell surface. Based on this, Whistler and coworkers proposed the "RAVE" (Relative Agonist signaling Versus Endocytosis) theory, stating that strong internalization would limit tolerance while sustained signaling would favor it. Probably the best studied change in intracellular signaling produced by chronic opioid administration is cAMP up-regulation. Acutely, this pathway is inhibited by opioids, but chronic exposure leads to a loss of inhibition of adenylate cyclase. This is due, in part, to a loss of the ability of the agonist-occupied receptor to activate Gi/o proteins and to an increased expression of certain types of adenylate cyclase, protein kinase A (PKA) and cAMP response element binding protein (CREB). Persistent opioid receptor activation also induces an increase in calcium channel activity, a decrease in the activation of G-coupled inwardly rectifying potassium channels (GIRKs), and a stimulation of the phospholipids signal transduction pathways. All these mechanisms have also been proposed to play a role in tolerance development. Several enzymes can be activated as a result of chronic opioid administration. Among them, phospholipase A2 (PLA2), cyclooxygenase (COX), in particular the COX-2 isoform, and nitric oxide synthase (NOS) are particularly relevant because their activation leads to an increase in prostaglandins and nitric oxide synthesis. Besides, repeated opioid agonist exposure induces an up-regulation of the cAMP-dependent protein kinase (PKA), the calcium-dependent protein kinase (PKC), the calcium calmodulin II dependent kinase and those kinases activated by mitogens (MAPKs). Phosphorylation by these kinases alters the functioning of many different target proteins, including NMDA receptors. When these glutamatergic receptors are phosphorylated, the Mg2+ block is removed and sodium and calcium ions can enter the cell. There is sound evidence indicating that NMDA receptor activation plays an important role in opioid analgesic tolerance because NMDA receptor antagonists prevent and/or delay its development in humans and animals. There is agreement in considering opioid analgesic tolerance as a complex phenomenon, but those changes resulting in an intracellular calcium increase seem to play a particularly relevant role. Since activation of certain physiological systems may antagonize some acute opioid effects, several investigators have proposed that, as a consequence of chronic opioid administration, endogenous antiopioid peptides are released to maintain the homeostasis. Among them, the best studied peptides are the Tyr-MIF-1 family of peptides, cholecystokinin (CCK), neuropeptide FF (NPFF) and orphanin FQ/nociceptin. Under physiological conditions these systems modulate opioid peptides, but the ba lance can be lost as a result of chronic opioid exposure. It has also been proposed that chronic opioid administration results in the activation of facilitatory pain descending pathways and that several neurotransmitter systems other than the adrenergic, serotonergic and opioidergic are affected by repeated morphine administration. Their relative impact in analgesic tolerance depends upon the species, the drug and the schedule of opioid administration. In preclinical studies, several drugs capable of preventing, decreasing or delaying analgesic tolerance when co-administered with opioids, have been identified. Based on this, several pharmacological strategies have been proposed to reduce tolerance. The following can be mentioned: a) administration of competitive and non-competitive NMDA receptor antagonists; b) co-administration of therapeutic opioid agonist doses with very low opioid antagonist doses; c) use of PKC inhibitors and COX inhibitors (in particular those with higher affinity for COX2 isoform); and d) co-administration of u. agonists with other agonists to induce receptor endocytosis thus preventing the induction of more long-lasting intracellular signaling changes. Among the pshysiological approaches, the proper dosification and administration schedule of opioids are crucial factors to prevent an artificial need of dose escalation.

Dipyrone potentiates morphine-induced antinociception in dipyrone-treated and morphine-tolerant rats.

Coadministration of morphine and dipyrone produces acute and chronic antinociceptive potentiation in drug-naive rats. In this work, the effectiveness of the combination was determined in rats pretreated with morphine or dipyrone. Nine groups of male rats received (i.v.) 3.1 mg/kg morphine, 600 mg/kg dipyrone, or the morphine-dipyrone combination twice a day for five administrations (three groups per treatment). From the 6th to the 10th administration, one group out of each treatment continued without change, while the other two were switched to one of the other two possible treatments. In morphine-tolerant rats, morphine plus dipyrone produced a transient antinociceptive potentiation. In dipyrone-treated animals, this combination produced a long-lasting potentiation. In animals only treated with the combination, antinociception was clear since the beginning, although it decreased after the 6th injection. No cross-tolerance was seen between morphine and dipyrone. These data suggest that dipyrone potentiates morphine-induced antinociception in dipyrone-treated as well as in morphine-tolerant rats.

Morphine and dipyrone co-administration delays tolerance development and potentiates antinociception.

This work analyses the time course of tolerance development and antinociceptive potentiation throughout repeated co-administration of morphine (an opioid receptor agonist) plus dipyrone (a non-steroidal anti-inflammatory drug) in the tail-flick test. Male Wistar rats were i.v. injected with morphine (3.1 mg/kg), dipyrone (600 mg/kg) or the combination morphine/dipyrone twice a day for 5 days. Dipyrone produced antinociceptive effects with a trend towards tolerance development at the end of the treatment. Morphine was initially effective, but complete tolerance developed after its fifth administration. The combination of morphine plus dipyrone produced a significant potentiation and longer duration of antinociceptive effects. The antinociceptive efficacy of morphine and dipyrone co-administration gradually decreased after the sixth injection. An additional group of rats treated with dipyrone for 11 days developed complete tolerance after the 19th administration. These data suggest that repeated co-administration of morphine plus dipyrone results in a delay of tolerance development and in a potentiation of their individual antinociceptive effects.

Metamizol potentiates morphine antinociception but not constipation after chronic treatment.

This work evaluates the antinociceptive and constipating effects of the combination of 3.2 mg/kg s.c. morphine with 177.8 mg/kg s.c. metamizol in acutely and chronically treated (once a day for 12 days) rats. On the 13th day, antinociceptive effects were assessed using a model of inflammatory nociception, pain-induced functional impairment model, and the charcoal meal test was used to evaluate the intestinal transit. Simultaneous administration of morphine with metamizol resulted in a markedly antinociceptive potentiation and an increasing of the duration of action after a single (298+/-7 vs. 139+/-36 units area (ua); P<0.001) and repeated administration (280+/-17 vs. 131+/-22 ua; P<0.001). Antinociceptive effect of morphine was reduced in chronically treated rats (39+/-10 vs. 18+/-5 au) while the combination-induced antinociception was remained similar as an acute treatment (298+/-7 vs. 280+/-17 au). Acute antinociceptive effects of the combination were partially prevented by 3.2 mg/kg naloxone s.c. (P<0.05), suggesting the partial involvement of the opioidergic system in the synergism observed. In independent groups, morphine inhibited the intestinal transit in 48+/-4% and 38+/-4% after acute and chronic treatment, respectively, suggesting that tolerance did not develop to the constipating effects. The combination inhibited intestinal transit similar to that produced by morphine regardless of the time of treatment, suggesting that metamizol did not potentiate morphine-induced constipation. These findings show a significant interaction between morphine and metamizol in chronically treated rats, suggesting that this combination could be useful for the treatment of chronic pain.