Combined Administration Of Morphine Research Articles

СОСТОЯНИЕ ДОФАМИНЕРГИЧЕСКОЙ СИСТЕМЫ ГОЛОВНОГО МОЗГА КРЫС ПРИ МОРФИН-АЛКОГОЛЬНОМ ПОСТИНТОКСИКАЦИОННОМ СИНДРОМЕ

Background. Opioid addiction, which has arisen against the background of previous alcoholism (or vice versa), is an urgent problem in clinical practice. The change in dopaminergic neuromediation after the withdrawal of the combined effect of ethanol and morphine is currently not clear what was the goal for our study. Purpose. Study of metabolites of the dopaminergic system in the cerebral cortex, striatum and midbrain of rats after different periods of withdrawal of 5-day morphine-alcohol intoxication. Material and methods. The experiments were carried out on 43 white outbred male rats. Using the HPLC method, the levels of metabolites of the dopaminergic system were determined after the withdrawal of the combined administration of morphine and ethanol. Results and conclusions. The severity of changes in metabolites of the dopaminergic system during morphinealcohol withdrawal is determined by the duration and region of the brain. One day after the withdrawal of both psychoactive substances in the striatum and cerebral cortex, a decrease in the concentration of dopamine was observed. In the long-term periods of abolition of intoxication with morphine and ethanol (3, 7 days), the processes of acceleration of dopamine turnover in the midbrain and a decrease in the concentration of the neurotransmitter in the striatum were revealed.

Changes in the dopaminergic system in the hypothalamus and midbrain of rats at chronic complex alcohol-morphine intoxication

Recently, there have been more and more indications of alcoholic pathology burdened by drug use and vice versa. It is evident that the dopamine system plays an important role in the development of addiction when using drugs and alcohol. Experimentally, the long-term combined effect of psychoactive substances on neuromendatory changes in the dopaminergic system in the brain is poorly understood and requires more detailed consideration.The aim of the study was to examine the changes in the dopaminergic system in the hypothalamus and midbrain of rats during chronic alcohol intoxication, as well as a complex administration of morphine and ethanol.The experiments were carried out on white outbred male rats. Using the HPLC method, the levels of dopamine and its metabolites were determined in the regions of the brain during chronic alcohol intoxication, as well as with a combined administration of morphine and ethanol with various durations (7, 14 and 21 days).Chronic alcohol intoxication led to the signs of acceleration of the dopamine turnover only in the hypothalamus on the 7th and 14th days and its accumulation during three weeks of alcoholization. In the midbrain, a decrease in the concentration of the neurotransmitter was revealed when ethanol was injected for 7 days. Co-administration of surfactants was accompanied by slightly different changes: complex 7- and 21-day alcohol-morphine intoxication is accompanied by the dopamine accumulation in the hypothalamus and the decrease in the neurotransmitter turnover in the midbrain on the 14th and 21st days.

P05.04 Morphine pretreatment improves the therapeutic efficacy of doxorubicin in an orthotopic model of human glioblastoma

AbstractIntroduction:Morphine is the most frequently employed analgesic in pain therapy and its use is well documented during antineoplastic agents administration. In addition, morphine is able to alter the neuronal and glial microenvironment, leading to the stroke of the Blood-Brain Barrier (BBB) and enhancing the access of molecules normally unable to cross it, as Doxorubicin (Dox).We have developed a xenograft mice model of human glioblastoma in order to verify the effectiveness of Dox alone or in association with morphine.Materials and Methods:Foxn1 mice were injected with U87MG-luc cells in the left lobe of the brain and treated with Dox (5 mg/kg and 2.5 mg/kg, weekly) with or without morphine (10 mg/kg, weekly).Intracranial tumor growth was quantified by Bioluminescence Imaging (BLI).Results:The data showed that only Dox 5mg/kg determined a significant regression of BLI in a xenograft mouse model of brain glioma while the lower dose of 2.5 mg/kg was not effective.The average BLI for Dox 5mg/kg was 5-fold lower than that measured for Dox 2.5mg/kg (P=0.0238) and morphine 10 mg/kg (P=0.0098) and 8 fold lower than vehicle (P=0.0012).However, when administered with morphine to brain xenograft in nude mice, Dox 2.5mg/kg showed a decreasing radiance values corresponding to decreasing tumor growth. The average BLI for Dox 2.5 mg/kg plus morphine was 5-fold lower than Dox 2.5mg/kg alone (P=0.0053) and 8-fold lower than vehicle (P=0.0004).Even more interesting, the average BLI for Dox 2.5mg/kg plus morphine was lower than Dox 5mg/kg during the whole experiment, indicating the effectiveness of combined administration of morphine and low doses of Dox as proper dosage to treat poor prognosis brain tumors.In addition, a weekly schedule (up to 5 weeks) with a combination of 10 mg/kg morphine and 2.5 mg/kg Dox did not cause a body weight loss of animals; rather, it induced a body weight gain of +7,98% as a clear signal of minimal toxicity.Conclusions:The present findings show that molecules as morphine are able to interfere with molecules normally unable to cross the BBB. This mechanism could be used for new approaches in therapy of refractory CNS tumors as glioblastoma.

Synergistic antinociceptive actions and tolerance development produced by morphine–fentanyl coadministration: Correlation with μ-opioid receptor internalization

It has been described that coadministration of opioids with low doses of other analgesics can reduce adverse effects and increase antinociception, but combinations of two μ-opioid receptor agonists have been poorly explored. The objective of this work was threefold: 1) to evaluate the antinociceptive combination of i.c.v. morphine and fentanyl at different doses; 2) to compare the antinociception produced by acute or repeated administration of an effective morphine dose (1μg) alone, or combined with a low fentanyl dose (1ng); and 3) to correlate these effects with μ-opioid receptor internalization in periaqueductal gray matter and locus coeruleus. Antinociception was evaluated by the tail-flick test and receptor internalization was analyzed by confocal microscopy in Wistar rats. Drug interactions were examined by administering combinations of opioids in 1:3, 1:1 and 3:1 ratios of their respective ED50 fractions. For tolerance and internalization studies, animals were i.c.v. injected only once (acute treatment) or twice a day until five administrations were completed. Our results show that morphine and fentanyl have synergistic effects. The combination of 1ng fentanyl with 1μg morphine increases the magnitude and duration of antinociception not only after a single injection, but also after five administrations when tolerance develops to morphine alone. Increased and long-lasting antinociception correlates positively with increased β-arrestin 2 activity and μ-opioid receptor internalization in periaqueductal gray matter and locus coeruleus. These results suggest that combined administration of morphine and fentanyl increases long-lasting antinociception and β-arrestin 2 signaling contributes to the combination effects.

Interactions of opioids with caffeine: evaluation by ambulatory activity in mice.

Morphine (up to 10 mg kg-1), buprenorphine (up to 0.1 mg kg-1), pentazocine (30 mg kg-1) and caffeine (up to 10 mg kg-1), significantly increased mouse ambulation. The combination of morphine, buprenorphine and pentazocine with caffeine generally enhanced the effect. Dopamine D1- and D2-receptor bockade, depletion of stored dopamine, and inhibition of dopamine synthesis could reduce the ambulation increased by single administration of morphine, buprenorphine and caffeine, and by combined administration of morphine and buprenorphine with caffeine. Although naloxone (0.1-3 mg kg-1) itself did not change mouse ambulation, at 3 mg kg-1, it reduced the effect of caffeine. The repeated administration of morphine (10 mg kg-1) induced a sensitization to the ambulation-increasing effect, and was inhibited by the combination of caffeine (10 mg kg-1) in the repeated administration schedule. The repeated administration of caffeine (10 mg kg-1) with buprenorphine (0.3 mg kg-1) resulted in a decrease in the effect to the level of caffeine alone. The development of cross-sensitization to morphine (10 mg kg-1) by the repeated treatment with buprenorphine (0.3 mg kg-1) was inhibited by caffeine (10 mg kg-1). Our results suggest that the dopaminergic systems are involved in the enhanced interaction of opioids having agonistic action on mu- or sigma-receptors with caffeine. However, it is also considered that, following the repeated administration, caffeine acts to reduce the sensitivity to the ambulation-increasing effect of opioids, probably inducing up-regulation of adenosinergic systems.

Attenuation of morphine tolerance and withdrawal syndrome by coadministration of nalbuphine

Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to and dependence on morphine by repeat application is a major problem in pain therapy. The purpose of the present study was to investigate whether combined administration of nalbuphine with morphine affects the development of tolerance to and dependence on morphine. We hypothesize that the use of nalbuphine, kappa-agonist may prove to be useful adjunct therapy to prevent morphine-induced undesirable effects in the management of some forms of chronic pain. Morphine (10 mg/kg) was injected to rats intraperitoneally for 5 day. The variable dose of nalbuphine (0.1, 1.0 and 5.0 mg/kg) was administered (i.p.) in combination with morphine injection. The development of morphine tolerance was assessed by measuring the antinociceptive effect with the Randall-Selitto apparatus. The development of dependence on morphine was determined by the scoring the precipitated withdrawal signs for 30 min after injection of naloxone (10 mg/kg, i.p.). Nalbuphine did not attenuate antinociceptive effect of morphine in rats. Interestingly, combined administration of morphine with nalbuphine (10:1) significantly attenuated the development of dependence on morphine. The elevation of [3H]MK-801 binding in frontal cortex, dentate gyrus, and cerebellum after chronic morphine infusion was suppressed by the coadministration of nalbuphine. In addition, the elevation of NR1 expression by morphine was decreased by the coadministration of nalbuphine in rat cortex. These results suggest that the coadministration of nalbuphine with morphine in chronic pain treatment can be one of therapies to reduce the development of tolerance to and dependence on morphine.

Behavioral interactions caused by combined administration of morphine and MK-801 in rats.

The NMDA antagonist MK-801 reportedly blocks experience-dependent changes in sensitivity to morphine, including tolerance to its analgesic actions and sensitization to its locomotor-stimulating effects. However, evidence in the existing literature suggests that some of MK-801's effects are additive (or synergistic) with those of morphine. Experiments were conducted to characterize the effects of acute and repeated administration of the combination of MK-801 and morphine on analgesia, locomotor activity, and drug discrimination in rats. In each experiment, rats were first tested repeatedly after treatment with the combination of MK-801 and morphine, and then after treatment with either drug alone. The analgesic effects of MK-801 combined with morphine were greater than those of morphine alone, but tolerance to the combination of drugs developed at a similar rate as to morphine alone. The locomotor-stimulating effects of MK-801 combined with morphine were also greater than those of either drug alone, and locomotor sensitization developed to the combination of drugs but not to either drug alone at the low doses used. Rats learned to discriminate a combination of MK-801 and morphine from vehicle as quickly as they learned to discriminate morphine alone from vehicle, but those trained with the combination of MK-801 and morphine responded primarily at the vehicle-appropriate lever when given either drug alone. Since behavioral adaptations readily occur in the presence of MK-801, it appears that NMDA antagonists fail to invariably block the cellular plasticity that underlies such adaptations. Rather, the expression of adaptations in drug sensitivity appears related, at least in part, to the continued presence of the discriminative stimulus cues that are present during conditioning. Although NMDA receptors are important for some forms of cellular plasticity, the present studies illustrate the difficulty in interpreting behavioral studies in which MK-801 is given with morphine.

Effects of opioid receptor antagonists on the effects of i.v. morphine on carrageenin evoked c-Fos expression in the superficial dorsal horn of the rat spinal cord

This study performed in freely moving rats evaluated the ability of specific opioid receptor antagonists to reverse the inhibitory effects of morphine on carrageenin-induced c-Fos expression in the spinal cord. Our study focused on the superficial dorsal horn (laminae I–II), which is the main termination site of nociceptive primary afferent fibers and is rich in opioid receptors. In order to replicate clinical routes of administration, all agents were administered intravenously (i.v.). As previously demonstrated, pre-administered i.v. morphine (3 mg/kg) produced a marked decrease (58±5%) in the number of Fos-LI neurones measured at 2 h after intraplantar (i.pl.) carrageenin (6 mg/150 μl) and yet was without influence on peripheral oedema. This decrease in c-Fos expression was completely blocked by combined administration of morphine with the μ-opioid receptor antagonist, [ d-Phe-Cys-Tyr- d-Orn-Thr-Pen-Thr-NH2] (CTOP-1+1 mg/kg). Naltrindole (NTI-1+1 mg/kg), a δ-opioid receptor antagonist partially blocked the effects of systemic morphine, so that the inhibitory effects of morphine after NTI injection are now 40±4%. However, this effect of NTI was weak since the depressive effects of morphine were still highly significant ( p<0.001). In contrast, nor-binaltorphimine (nor-BNI-1+1 mg/kg), a κ-opioid receptor antagonist, had no significant effect on the effects of morphine. These results indicate the major contribution of μ-opioid receptors to the antinociceptive effects of systemic morphine at the level of the superficial dorsal horn. The observed effect of NTI is not necessarily related to a direct action of morphine on δ-opioid receptors and some possible actions of this antagonist are discussed.

Intense cold noxious stimulation of the rat hindpaw induces c- fos expression in lumbar spinal cord neurons

This study evaluated Fos-like immunoreactivity in lumbar spinal cord neurons following intense cold stimulation and then the modifications induced by opioid administration. Under urethane anaesthesia, the rat's right foot was stimulated by holding it in a regulated temperature bath at 15, 10, 0, −10, −15, −17.5 or −20°C. There was no or little Fos-like immunoreactivity in lumbar spinal cord neurons when the paw was at temperatures between 15 and −10°C (0–5 Fos-like immunoreactive neurons/section). The threshold to induce consistent c- fos expression was −15°C. From −15 to −20°C, the number of Fos-like immunoreactive neurons increased with decreases in temperature. At −20°C, Fos-like immunoreactive neurons were numerous in L3 and L4 segments, in laminae I–II (≈60 Fos-like immunoreactive neurons/section) and to a lesser extent in laminae V–VI (≈20). Almost no Fos-like immunoreactivity was present in laminae III–IV (< 5). At −20°C, the number of Fos-like immunoreactive neurons increased with the duration of the stimulation. The number of Fos-like immunoreactive neurons induced by the cold stimulation temperatures was significantly decreased by pretreatment with 10 mg/kg s.c. morphine and moderately decreased by 5 mg/kg s.c. This effect was antagonized by the combined administration of morphine (10 mg/kg s.c.) and naloxone (2 mg/kg s.c.). Naloxone (2 mg/kg s.c.) significantly increased the number of Fos-like immunoreactive neurons induced by −20°C as compared to saline-injected rats. This study showed that Fos-like immunoreactivity distribution is in good agreement with the location of neurons receiving noxious inputs and that the threshold to induce c- fos expression with cold was unexpectedly low at −15°C. Taking into account, on the one hand, previous investigations using the same technique using noxious heat stimulation and, on the other hand, electrophysiological and psychophysiological studies using cold stimulation in animals and humans, our results suggest that Fos-like immunoreactivity induced by extremely cold stimulation, which seems to reproduce frostbite, may reflect activation of nociceptors due to vasoconstriction.

The combined effects of morphine and d-amphetamine on the threshold for brain stimulation reward

The effect of morphine and d-amphetamine co-administration on the threshold for rewarding intracranial electrical stimulation was studied in rats with electrodes stereotaxically implanted in the medial forebrain bundle-lateral hypothalamic or ventral tegmental area of the brain. Thresholds were determined by means of a rate-independent psychophysical method. Individually, morphine and d-amphetamine both caused a dose-related lowering of the reward threshold. Low doses of morphine or d-amphetamine which were ineffective or minimally effective in lowering the reward threshold were then tested with various doses of either d-amphetamine or morphine, respectively. In both cases, the combined administration of morphine and d-amphetamine resulted in a lowering of the reward threshold that was greater than for the corresponding doses of morphine and d-amphetamine when given alone. Given that increased sensitivity for rewarding brain stimulation has been suggested to be an animal model of drug-induced euphoria, this effect is congruent with the reported increase in the degree of euphoria produced when amphetamine is used in conjunction with opiate drugs.

Mechanism of hematocrit increase induced by the combined administration of morphine and Adriamycin: Role of histamine release

The mechanism by which morphine interacts with Adriamycin to increase hematocrit has been investigated in mice. Treatment with Adriamycin (12.8 mg/kg, iv) or morphine (20 mg/kg, sc) resulted in slight increases in hematocrit 30 min postdose, while animals given sc morphine 30 min prior to iv Adriamycin exhibited significant increases in hematocrit as early as 1 min post-Adriamycin. The hematocrit increase reached maximal levels 12 min post-Adriamycin and returned to basal values 4 hr postdose. Splenectomizing animals prior to morphine and Adriamycin treatment had no effect on the drug-induced hematocrit increase. This indicates that red cell release from splenic contracture is not the mechanism for the hematocrit increase. Measurement of plasma histamine levels following drug treatment demonstrated a marked and rapid rise in plasma histamine levels reaching maximal values 1 min post-Adriamycin. Adriamycin alone triggered this release; however, morphine pretreatment resulted in a higher maximum and more prolonged elevation of plasma histamine levels. Treatment with pyrilamine (3.1–50 mg/kg, ip) prior to morphine and Adriamycin administration partially reversed drug-induced hematocrit increase and protected against resultant lethality. Cimetidine (50–200 mg/kg, ip) treatment was not effective. The temporal relationship between hematocrit and histamine increases suggests a cause/effect relationship between released histamine and hematocrit elevation. Protection by pyrilamine and not cimetidine further supports this cause/effect relationship and indicates the effect is mediated via histamine type 1 receptors.

Evidence for multiple serotonergic influences on LH release in ovariectomized rats and for modulation of their relative effectiveness by estrogen.

Both opiates and serotonin (5HT) are known to inhibit LH release in ovariectomized rats, and estrogen has been shown to reverse certain serotonergic effects. Therefore studies were undertaken to compare the effects of morphine and the serotonin agonist 5-methoxy-N,N-dimethyltryptamine (5MEODMT) on LH release in ovariectomized rats with and without estrogen priming. Serial blood samples were collected via jugular cannulae before and 5, 15, 30 and 60 min after intravenous administration of morphine, 5MEODMT or both to rats receiving no pretreatment, or a serotonin receptor antagonist (methysergide, METH; or ketanserin, KET) 60 min earlier. In the absence of estrogen, morphine inhibited LH release, and the response was delayed by METH or abolished by KET, suggesting mediation by serotonin2 (5HT2) receptors. 5MEODMT alone failed to alter the release of LH significantly, but apparently activated both stimulatory and inhibitory serotonergic systems. Blockade of 5HT2 receptors with KET enabled an inhibitory system to prevail. No significant changes in LH concentrations were observed following combined administration of morphine and 5MEODMT. Similarly, in estrogen-primed rats morphine appeared to activate both inhibitory (5HT2) and stimulatory (5HT1) systems, resulting in no net change unless the inhibitory system had been antagonized by KET. Administration of 5MEODMT alone or in combination with morphine resulted in a strong stimulatory effect which appeared to be mediated by 5HT1 receptors. These results suggest the existence of a multiplicity of serotonergic influences on the release of LH in the rat, not only in terms of particular species of 5HT receptors, but also in neuronal connectivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine-halothane interaction in rats.

The effects of morphine, halothane, and their various combinations on the purposeful movement (PM) response and the heart rate (HR) increase caused by noxious stimulation were studied in 250 rat experiments. Doses that block the PM and HR responses for the single agent and for combinations were determined with a probit procedure and compared with an isobolographic analysis. As was evidenced by the PM response, the combined anesthetic effect of morphine and halothane, with some deviations, may be defined as additive. It also was found that the combined administration of morphine and halothane results in an antagonism for suppression of the HR increase to noxious stimulation. Halothane antagonized morphine to a much greater extent than morphine to halothane.

Effect of morphine on the heart rate response to noxious stimulation: Interaction with halothane and naloxone

The effect of morphine on the heart rate increase, in response to noxious somatic stimulation, was studied in 125 rat experiments. It was found that halothane, in a subanesthetic concentration of 0.3 vol%, profoundly weakened the effect of morphine on the heart rate response. As a result, the morphine ED 50 value for blockade of the heart rate response was increased from 5.9 to 46.1 mg/kg ( P < 0.001). Naloxone in a dose of 0.05 mg/kg increased the morphine ED 50 value for blockade of the heart rate response 11-fold (morphine was administered without halothane). However, the same dose of naloxone did not change the morphine ED 50 value obtained with combined administration of morphine and halothane. An increase in the naloxone dosage (up to 1 mg/kg) was necessary to demonstrate the naloxone antagonistic effect (8-fold increase in the morphine ED 50 value) when morphine was given with halothane. It has been suggested that the effect of morphine on the heart rate response to noxious stimulation results primarily from the activation of inhibitory control mechanisms concerned with this response (indirect effect). Halothane depresses the inhibitory control mechanisms and, therefore, weakens the effect of morphine. A significant increase in doses of morphine is needed to provide the direct antinociceptive effect.

Cellular aspects of transcapillary exchange.

Mise au point bibliographique sur l'organisation de la paroi capillaire et de la membrane des cellules de ces capillaires ainsi que sur les processus d'endocytose et de transcytose

In vivo interaction of morphine and endogenous opiate-like peptides.

Abstract In the csf of rats, the concentration of peptides, reacting with antibody to leu-enkephalin, was determined by radioimmunoassay. Intravenous injection of morphine caused a biphasic response, i.e. an immediate and a delayed rise of the level of such immunoreactive peptides in the csf. After i.v. naloxone, only the late peak was observed. Combined administration of morphine and naloxone delayed the appearance of the first peak, expected after morphine injection; the second peak did not show within 2 – 3 hours. The results are interpreted by assuming release of enkephalins and related peptides from two sites, viz. synaptic clefts and intracellular pools.