Browsing by Subject "morphine"

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  • Herkkola, Hennariia (Helsingfors universitet, 2018)
    The nucleus accumbens (NAc) is located in the ventral striatum and plays a critical role in drug addiction. NAc receives dopaminergic projections from ventral tegmental area (VTA) which is activated after administration of various abused drugs. Activation of VTA increases the release of dopamine in NAc. Increased dopamine levels induce the release of acetylcholine from striatal cholinergic interneurons. These cholinergic interneurons have been related to the development of addiction and other emotion-related disorders such as depression. Previous studies have shown that a lesion of cholinergic interneurons led to an increase in morphine-induced conditioned place preference in mice. Moreover, an activation of cholinergic interneurons by designer receptors (DREADD) has reduced food consumption motivated by food restriction. The purpose of this study was to investigate whether accumbal cholinergic interneurons mediate alcohol- and morphine-induced conditioned place preference and locomotor activity. The activation of cholinergic interneurons was controlled using DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology. DREADDs are G protein-coupled receptors. Cellular function and activation can be modulated by these receptors. DREADDs are activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Fluorescent protein, mCherry, is attached to DREADDs so that the expression of receptors in brain tissue can be observed. Cre-spesific adeno-associated viruses (AAV) with DREADD gene were injected bilaterally to the nucleus accumbens of ChATcre mice in stereotactic surgery. The effects of alcohol and morphine were tested with conditioned place preference procedure. Mice were divided to three groups after DREADDs: activating receptor Gq (n = 10), inhibiting receptor Gi (n = 9) and control mC (n = 9). There were both male and female mice in every group. Alcohol did not induce conditioned place preference in any group. The locomotor activity of mice significantly increased after alcohol injection compared to saline injection. However, cholinergic interneurons had no effect on the increased locomotor activity. Morphine-induced conditioned place preference was expressed in every group but there were no significant differences between DREADDs and control group when the first 15 minutes and the whole 30 minutes of the place preference test was analysed. Though, Gq-receptor seemed to decrease the place preference compared to control group when the place preference test was observed in five minute intervals. Morphine also significantly increased the locomotor activity of mice, but there were no differences between the groups. Sex had no influence on the place preference, but female mice were more active than male mice during the alcohol conditioning and the alcohol place preference test. The locomotor activity of female mice also increased more than the activity of male mice after morphine injection. The effect of accumbal cholinergic interneurons on alcohol-induced conditioned place preference remained unclear. Activation of cholinergic interneurons suppressed morphine-induced conditioned place preference compared to control group but not enough so that the effect could be seen during the whole place preference test. The mice were same in the morphine test as in the alcohol test so the mice were conditioned to alcohol before morphine and therefore the results of morphine-induced conditioned place preference are not reliable.
  • Vashchinkina, Elena; Piippo, Ossi; Vekovischeva, Olga; Krupitsky, Evgeny; Ilyuk, Ruslan; Neznanov, Nikholay; Kazankov, Kirill; Zaplatkin, Igor; Korpi, Esa R. (2018)
    The gabapentinoid pregabalin is a rapid-acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its unknown addictive risk and rising number of mortalities after pregabalin self-medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. After the treatment of mice with pregabalin and morphine, we used electrophysiology to study neuroplasticity in midbrain slices, self-administration and conditioned place preference tests to investigate the rewarding potential of pregabalin and naloxone-precipitated morphine withdrawal to evaluate opioid withdrawal symptoms. Further, we ran a pilot single-blind, randomized, controlled trial (34 heroin addicts) to evaluate the efficacy and safety of pregabalin in the treatment of opioid withdrawal syndrome. Pregabalin alone did not induce glutamate receptor neuroplasticity of dopamine neurons in the ventral tegmental area, but pre-treatment with pregabalin suppressed morphine-induced neuroplasticity, hyperlocomotion and morphine self-administration. Pregabalin administration after chronic morphine exposure failed to induce any rewarding effects. Instead, pregabalin suppressed withdrawal symptoms in both morphine-treated mice and opioid addicts and was well tolerated. Intriguingly, pregabalin administration after a low dose of morphine strongly facilitated ventral tegmental area neuroplasticity and led to increased conditioned place preference. Pregabalin appears to have the efficacy to counteract both reinforcing and withdrawal effects of opioids, but it also has a potentiating effect when given to mice with existing opioid levels.
  • Blomqvist, Kim Juhani; Dudek, Katarzyna; Viisanen, Hanna; Mätlik, Kert; Ahlström, Fredrik Harry Gustav; Laitila, Jouko; Kalso, Eija Anneli; Rauhala, Pekka Veli; Lilius, Tuomas Olavi (2022)
    Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.
  • Miettinen, Ville (Helsingin yliopisto, 2020)
    Pedunculopontine tegmental nucleus (PPTg) has been connected to many different brain functions. Lesions in this region have been demonstrated to have effects on drug related behavior, learning and locomotion. Furthermore, glutamatergic projections to VTA have been found in earlier studies. VTA is one of the most important brain regions related to feeling of reward. Thus, it is plausible that glutamatergic cells are the ones that are responsible for these alterations in drug related behaviour. Additionally, there are efferents to basal ganglia and regions related to them, which indicates that PPTg is likely to possess some functions related to locomotion. The aim of this study was to explore what kind of differences in food consumption, spontaneous locomotion, morphine induced locomotion and morphine induced conditioned place preference result from modulation of activity of the glutamatergic neurons of the PPTg in mice. In this study DREADD-method was used. This method allowed for both excitation and inhibition of the neurons. This method involves injection viral vector stereotactically to the desired brain region, which leads to expression of artificial receptor in specific type of neurons. These receptors can then be activated by injecting clozapine-Noxide(CNO) intraperitoneally. There were two test groups, one got receptor that activates the neuron when activated, other got one that inhibits the neuron. Control group got receptor that does not react to CNO. In the tests conducted, there was no difference in the amount of food consumed or distance moved spontaneously. In the conditioned place preference experiment, there was no significant difference in distance moved between groups. However, both of the test groups expressed weaker preference to the morphine-paired environment when compared to the control group. This could be explained by reinforcing effects of morphine being mediated through glutamatergic neurons of the PPTg.
  • Lilius, T.; Kangas, E.; Niemi, M.; Rauhala, P.; Kalso, E. (2018)
    Background: Ketamine attenuates morphine tolerance by antagonising N-methyl-D-aspartate receptors. However, a pharmacokinetic interaction between morphine and ketamine has also been suggested. The interaction between oxycodone and ketamine is unclear. We studied the effects of ketamine and norketamine on the attenuation of morphine and oxycodone tolerance focusing on both the pharmacodynamic and pharmacokinetic interactions. Methods: Morphine 9.6 mg day(-1) or oxycodone 3.6 mg day(-1) was delivered to SpragueeDawley rats by subcutaneous pumps. Once tolerance had developed, the rats received subcutaneous injections of ketamine or norketamine. Tail-flick, hot-plate, and rotarod tests were performed. Drug concentrations were measured with high-performance liquid chromatographyetandem mass spectrometry. Results: Anti-nociceptive tolerance to morphine and oxycodone developed similarly by Day 6. Acute ketamine 10 mg kg(-1) and norketamine 30 mg kg(-1) attenuated morphine tolerance for 120 and 150 min, respectively, whereas in oxycodonetolerant rats the effect lasted only 60 min. Both ketamine and norketamine increased the brain and serum concentrations of morphine, and inhibited its metabolism to morphine-3-glucuronide, whereas oxycodone concentrations were not changed. Morphine, but not oxycodone, pretreatment increased the brain and serum concentrations of ketamine and norketamine. Ketamine, but not norketamine, significantly impaired the motor coordination. Conclusions: Ketamine and norketamine attenuated morphine tolerance more effectively than oxycodone tolerance. Ketamine and norketamine increased morphine, but not oxycodone brain concentrations, which may partly explain this difference. Norketamine is effective in attenuating morphine tolerance with minor effects on motor coordination. These results warrant pharmacokinetic studies in patients who are co-treated with ketamine and opioids.
  • Ojala, Katja (Helsingfors universitet, 2010)
    Glutamate is the principal excitatory neurotransmitter in the central nervous system. Glutamatergic neurotransmission plays a central role in the development and maintenance of drug addiction. Glutamate interacts with other neurotransmitters such as dopamine in the actions concerning addiction. During the development of drug addiction, plastic changes in the neuronal connections related to memory and learning occur for example in the amount of synapses and in the efficacy of their action. Glutamatergic AMPA receptor and especially its GluA1 subunit are thought to be included in the neurobiological mechanisms related to drug addiction. Compulsive drug craving and relapses to drug use after a period of abstinence are central problems among people suffering drug addiction. Conditioned place preference is a technique that is used to study motivational properties of drugs in experimental animals. The aim of this master's thesis was to examine the importance of glutamatergic AMPA receptor GluA1 subunit in the morphine-induced place preference and in its extinction and reinstatement behaviour. Locomotor activity of mice was studied during all the phases of experiment. Glutamatergic AMPA receptor GluA1 subunit-deficient (GluA1-/-) and their control (wildtype) mice, based on C57BL/6J mouse strain, were used in the experiments. During the conditioning phase, the mice were trained to associate the effects of morphine (20 mg/kg) with a specific environment. After conditioning, the extinction with morphine paired conditioning environment was assessed by giving saline (0,9 % NaCl solution) to mice. The extinction phase was followed by reinstatement test, in which mice were given morphine (20 mg/kg). The seeking of animals with morphine paired conditioning environment described drug-seeking during different phases of experiment. GluA1-/- mice were more hyperactive when placed in the testing environment compared to the wildtype mice. However, the morphine-induced locomotor activity did not differ between genotypes. Locomotor activity of both genotypes was sensitized equally in consequence of repeated morphine exposures. Morphine induced place preference in both genotypes. Furthermore, the extinction of morphine place preference happened in both genotypes. However, the results of reinstatement test differed partly between genotypes. The place preference was reinstated by morphine in wildtype mice, but not in GluA1-/- mice, when using repeated testing extinction method. Instead of place preference, wildtype mice exhibited place aversion, when extinction method was saline conditioning. As a result of these experiments, extinction method can have an impact on the results of reinstatement test and conclusions cannot be done on the importance of GluA1 subunit in morphine reinstatement. In conclusion, the results of place preference experiments support the conception that GluA1 subunit is not significant in morphine conditioning. However, based on these experiments, GluA1 subunit is not important in morphine extinction, as one might assume on the basis of literature. GluA1 subunit may have an importance in morphine reinstatement, although the results of reinstatement test were partly contradictory.
  • Miro, Oscar; Gil, Victor; Martin-Sanchez, Francisco J.; Herrero-Puente, Pablo; Jacob, Javier; Mebazaa, Alexandre; Harjola, Veli-Pekka; Rios, Jose; Hollander, Judd E.; Frank Peacock, W.; Llorens, Pere; ICA-SEMES Res Grp (2017)
    OBJECTIVE: The objective was to determine the relationship between short-term mortality and intravenous morphine use in ED patients who received a diagnosis of acute heart failure (AHF). METHODS: Consecutive patients with AHF presenting to 34 Spanish EDs from 2011 to 2014 were eligible for inclusion. The subjects were divided into those with (M) or without IV morphine treatment (WOM) groups during ED stay. The primary outcome was 30-day all-cause mortality, and secondary outcomes were mortality at different intermediate time points, in-hospital mortality, and length of hospital stay. We generated a propensity score to match the M and WOM groups that were 1:1 according to 46 different epidemiological, baseline, clinical, and therapeutic factors. We investigated independent risk factors for 30-day mortality in patients receiving morphine. RESULTS: We included 6,516 patients (mean age, 81 [SD, 10] years; 56% women): 416 (6.4%) in the M and 6,100 (93.6%) in the WOM group. Overall, 635 (9.7%; M, 26.7%; WOM, 8.6%) died by day 30. After propensity score matching, 275 paired patients constituted each group. Patients receiving morphine had a higher 30-day mortality (55 [20.0%] vs 35 [12.7%] deaths; hazard ratio, 1.66; 95% CI, 1.09-2.54; P=.017). In patients receiving morphine, death was directly related to glycemia (P=.013) and inversely related to the baseline Barthel index and systolic BP (P=.021) at ED arrival (P=.021). Mortality was increased at every intermediate time point, although the greatest risk was at the shortest time (at 3 days: 22 [8.0%] vs 7 [2.5%] deaths; OR, 3.33; 95% CI, 1.40-7.93; P=.014). In-hospital mortality did not increase (39 [14.2%] vs 26 [9.1%] deaths; OR, 1.65; 95% CI, 0.97-2.82; P=.083) and LOS did not differ between groups (median [interquartile range] in M, 8 [7]; WOM, 8 [6]; P=.79). CONCLUSIONS: This propensity score-matched analysis suggests that the use of IV morphine in AHF could be associated with increased 30-day mortality.
  • Ojanen, Sami (2006)
    Repeated use of drugs of abuse induces permanent changes in the brain that together with environmental factors can promote the development of addiction. Addiction to alcohol or drugs is a chronic disease that is characterized by a compulsion to seek and take the drug, loss of control in limiting intake, continued use despite obvious harm, and recurrent relapses. Behavioral animal models of addiction are invaluable tools for evaluating the neuroadaptations underlying these behaviors. Behavioral sensitization is a form of neuronal plasticity where repeated administration of drugs induces a progressive and enduring enhancement in their behavioral and neurochemical effects. The aim of this study was to investigate differences in susceptibility to morphine-induced behavioral and neurochemical sensitization in alcohol-preferring AA and alcohol-avoiding ANA rat lines, and to clarify its role on voluntary intake of ethanol. In vivo microdialysis was used to examine dopaminergic, glutamatergic and GABAergic neurotransmission in the brain. Interactions between behavioral sensitization and voluntary ethanol intake were assessed in AA rats during and after the rats were sensitized to morphine. The results showed that AA rats are more susceptible to morphine-induced behavioral sensitization than ANA rats. Neurochemical studies indicated a dissociation between the locomotor stimulant effects of morphine and extracellular levels of dopamine in the nucleus accumbens. In addition, sensitization to morphine affected glutamatergic transmission in the ventral tegmental area differently in AA and ANA rats. In contrast, extracellular levels of GABA differed neither between the lines nor between morphine- sensitized rats and controls. Glutamatergic transmission is therefore potentially involved in the higher susceptibility to morphine-induced sensitization in AA rats relative to ANAs, but the role of GABA remains unclear. Morphine-induced behavioral sensitization or other long-term adaptations in the brain induced by repeated morphine administration were not critically involved in the regulation of voluntary ethanol drinking. Opioid receptor activation with morphine injection, however, was shown to dramatically increase ethanol drinking in morphine-sensitized AA rats. Thus, the neuronal mechanisms underlying behavioral sensitization to morphine probably are distinct from those mediating ethanol reinforcement. In contrast, when given an additional morphine injection, reinforcing effects of ethanol were enhanced in AA rats sensitized to morphine.
  • Viisanen, Hanna; Lilius, Tuomas O.; Sagalajev, Boriss; Rauhala, Pekka; Kalso, Eija; Pertovaara, Antti (2020)
    Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid. is not yet known. Ketamine, an N-methyl-o-aspartate (NMDA) receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid-tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone. NEW & NOTEWORTHY Morphine and oxycodone are two clinically used strong opioids. Chronic treatment with oxycodone as well as morphine can lead to analgesic tolerance and paradoxical hyperalgesia. Here we show that an N-methyl-n-aspartate receptor-dependent pronociceptive change in discharge properties of rostroventromedial medullary neurons controlling spinal nociception has an important role in antinociceptive tolerance to morphine but not oxycodone. Interestingly, chronic oxycodone did not induce pronociceptive changes in the rostroventromedial medulla.
  • Morlion, Bart; Schaefer, Michael; Betteridge, Neil; Kalso, Eija (2018)
    Objective: Acute postoperative pain is experienced by the majority of hospitalized patients undergoing surgical procedures, with many reporting inadequate pain relief and/or high levels of dissatisfaction with their pain management. Patient-controlled analgesia (PCA) ensures patient involvement in acute pain control, a key component for implementing a quality management system. This narrative article overviews the clinical evidence for conventional PCA and briefly discusses new, non-invasive PCA systems, namely the sufentanil sublingual tablet system (SSTS) and the fentanyl iontophoretic transdermal system (FITS). Methods: A Medline literature search (patient-controlled analgesia and acute postoperative pain) was conducted to 1 April 2017; results from the main clinical trials are discussed. Additional literature was identified from the reference lists of cited publications. Results: Moderate to low quality evidence supports opioid-based intravenous PCA as an efficacious alternative to non-patient-controlled systemic analgesia for postoperative pain. However, despite the benefits of PCA, conventional intravenous PCA is limited by system-, drug- and human-related issues. The non-invasive SSTS and FITS have demonstrated good efficacy and safety in placebo- and intravenous morphine PCA-controlled trials, and are associated with high patient/healthcare practitioner satisfaction/ease of care ratings and offer early patient mobilization. Conclusions: Evidence-based guidelines for acute postoperative pain management support the use of multimodal regimens in many situations. As effective and safe alternatives to conventional PCA, and with the added benefits of being non-invasive, easy to use and allowing early patient mobilization, the newer PCA systems may complement multimodal approaches, or potentially replace certain regimens, in hospitalized patients with acute postoperative pain.
  • Kiiskinen, Tuomo; Korpi, Esa R.; Aitta-aho, Teemu (2019)
    Extinction and reinstatement of morphine-induced conditioned place preference were studied in glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor GluA1 subunit-deficient mice (global GluA1-KO mice). In line with previous findings, both acquisition and expression of conditioned place preference to morphine (20 mg/kg, subcutaneously) were fully functional in GluA1 KO mice compared with wild-type littermate controls (GluA1-WT), thus enabling the study of extinction. With a 10-session extinction paradigm, the GluA1 KO mice showed complete extinction similar to that of the GluA1-WT mice. Morphine-induced reinstatement (10 mg/kg, subcutaneously) was detected in both mouse lines. GluA1 KO mice moved more during all the phases of the experiment, including the place conditioning trials, extinction sessions, and place preference tests. The results suggest that the GluA1 subunit may be dispensable or prone to compensation at the neural circuitries delineating extinction and reinstatement. The GluA1 KO mice show altered long-term between-session habituation, which extends longer than previously anticipated.