Modulation of dopaminergic neurotransmission by morphine in the rat

The pleasant effects of opium were already known 6000 years ago and opium has been used for medical purposes for at least 3500 years. Opium, and its r.1ain constituent morphine, evoke a feeling of well-being and always relieve pain of any origin, in other words, a perfect analgesic and euphoric drug. However, there are unpleasant repercussions. Thus, the pleasant effects are followed by a period of dysphoria. With the first, moderate dose of opiate this rebound is not important. But euphoric and analgesic effects disappear with repeated administration unless the dose is steadily increased. When the opiate is withcirawn after repeated administration of high doses, the dysphoric rebound wi 11 gain dangerous proportions and this is one of the reasons for continued (addicted) use of the opiate. Thus, the perfect analgesic and euphoric drug produces a perfect dependence. One of the most important stimuli to the promotion of research into the mechanism of action of opiates is the desire to control opiate-dependence. Such control would help two groups of users: those who need a strong analgesic would not necessarily become dependent and those who become dependent would not necessarily always need opiates. The acute effects of morphine are highly interrelated phenomena such as analgesia and euphoria, while dependence is ascribed to an adaptation of the cells of the body. In order to relate or dissociate these effects of opiates it is necessary to analyse the eel lular and molecular events related to the acute effects of the opiate. If these cellular and molecular events are the same as those underlying opiate-dependence, it will not be possible to dissociate the analgesic and euphoric effects of opiates from their ability to produce dependence. However, if it appears that differences do exist between the mechanism of these two opiateinduced phenomena then control of opiate-dependence may be possible. In the experiments described here, the effects of acute morphine administration on dopaminergic neurons in the rat were investigated. Dopamine is an important neurotransmitter in 1 imbic and extrapyramidal brain areas and plays an important role in the integration of emotional responses. Furthermore, the analgesic and rewarding (euphoric?) properties of morphine have been related inter alea to interactions with dopaminergic systems. An attempt has been made to analyse molecular mechanisms involved in the action of morphine on dopaminergic neurons in different brain areas and to analyse the relation of both these actions and behavioural responses to acute morphine administration

Assessing the environmental impacts of production- and consumption-side measures in sustainable agriculture intensification in the European Union

Sustainable agricultural intensification (SI) is an important strategy to respond to the combined challenge of achieving food security and providing public goods and ecosystem services to society, including mitigation and adaptation of climate change. Sustainable intensification includes a wide range of measures at both the supply and demand-side of agricultural production. However, currently, it is unclear what are the most effective and priority measures. This study assesses the potential of different SI measures for reducing GHG (greenhouse gas) emissions and increasing land use efficiency in the European Union's agriculture sector. A scenario approach was combined with life cycle analysis to quantify the environmental impacts of a number of different SI measures. The sustainable intensification measures assessed in this study are: 1) changing human diet; 2) using food waste in livestock diets; 3) shifting from monoculture cropping to crop rotation, and, 4) incorporating crop residues into the soil. The results reveal that the studied SI measures have the potential to increase land use savings, ranging from 0.06 to 3.32 m2/person/day, while GHG emission savings ranging from 71 to 1872 g CO2-eq/person/day can be achieved at EU level. Among these SI measures, changing human diet showed a remarkably high reduction of environmental impacts. On the contrary, increased GHG emission savings in the other SI measures (i.e. crop residue incorporation in the field and replacing soybean meal in conventional feed by food waste-based feed) are counter effected by increased GHG emissions in the energy sector due to reduction of feedstock availability for bioenergy production. The approach used in this study allows the assessment of both the production and consumption-side SI measures and allows the identification of the most effective SI measures and their potential trade-offs

From “getting things right” to “getting things right now”: Developing COVID-19 guidance under time pressure and knowledge uncertainty

Background - At the start of the COVID-19 pandemic, guidance was needed more than ever to direct frontline healthcare and national containment strategies. Rigorous guidance based on robust research was compromised by the emergence of the pandemic and the urgency of need for guidance. Rather than aiming to “get guidance right”, guidance developers needed to “get guidance right now”. Aim - To examine how guidance developers have responded to the need for credible guidance at the start of the COVID-19 pandemic. Methods - An exploratory mixed-methods study was conducted among guidance developers. A web-based survey and follow-up interviews were used to examine the most pertinent challenges in developing COVID-19 guidance, strategies used to address these, and perspectives on the implications of the COVID-19 pandemic on future guidance development. Results - The survey was completed by 46 guidance developers. Survey findings showed that conventional methods of guidance development were largely unsuited for COVID-19 guidance, with 80% (n = 37) of respondents resorting to other methods. From the survey and five follow-up interviews, two themes were identified to bolster the credibility of guidance in a setting of extreme uncertainty: (1) strengthening end-user involvement and (2) conjoining evidence review and recommendation formulation. 70% (n = 32) of survey respondents foresaw possible changes in future guidance production, most notably shortening development time, by reconsidering how to balance between rigour and speed for different types of questions. Conclusion - “Getting guidance right” and “getting guidance right now” are not opposites, rather uncertainties are always part of guidance development and require guidance developers to balance scientific robustness with usability, acceptability, adequacy and contingency. This crisis points to the need to acknowledge uncertainties of scientific evidence more explicitly and points to mechanisms to live with such uncertainty, thus extending guidance development methods and processes more widely

Dose-dependent effects of intravenous lorazepam on cardiovascular activity, plasma catecholamines and psychological function during rest and mental stress

Dose-dependent effects of intravenously administered lorazepam on psychophysiological activity during rest and mental stress were studied in order to examine differential responses to doses which may induce anxiolysis or sedation. In a double-blind randomized cross-over study, nine male volunteers participated in a placebo and a lorazepam session, during which the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.06, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). Heart rate showed a dose-dependent decrease during rest with an ED50 of 0.13 mg lorazepam, while lorazepam had no effect on the cardiovascular and plasma catecholamine response magnitudes to the CWT. Subjective fatigue and reaction time increased significantly after 0.94 mg lorazepam, while at the same dose vigor decreased; state anxiety after the CWT was not influenced by lorazepam. These data show differential effects of lorazepam on cardiovascular, biochemical and psychological function. While heart rate was suppressed at low doses during rest and reaction time and subjective fatigue increased at doses which induced sedation, state anxiety and physiological response patterns to the CWT were not influenced by lorazepam

Functional Locomotor Consequences of Uneven Forefeet for Trot Symmetry in Individual Riding Horses

ABSTRACT: Left-right symmetrical distal limb conformation can be an important prerequisite for a successful performance, and it is often hypothesized that asymmetric or uneven feet are important enhancing factors for the development of lameness. On a population level, it has been demonstrated that uneven footed horses are retiring earlier from elite level competition, but the biomechanical consequences are not yet known. The objectives of this study were to compare the functional locomotor asymmetries of horses with uneven to those with even feet. Hoof kinetics and distal limb kinematics were collected from horses (n = 34) at trot. Dorsal hoof wall angle was used to classify horses as even or uneven (1.5° difference between forefeet respectively) and individual feet as flat (55°). Functional kinetic parameters were compared between even and uneven forefeet using MANOVA followed by ANOVA. The relative influences of differences in hoof angle between the forefeet and of absolute hoof angle on functional parameters were analysed using multiple regression analysis (P<0.05). In horses with uneven feet, the side with the flatter foot showed a significantly larger maximal horizontal braking and vertical ground reaction force, a larger vertical fetlock displacement and a suppler fetlock spring. The foot with a steeper hoof angle was linearly correlated with an earlier braking-propulsion transition. The conformational differences between both forefeet were more important for loading characteristics than the individual foot conformation of each individual horse. The differences in vertical force and braking force between uneven forefeet could imply either an asymmetrical loading pattern without a pathological component or a subclinical lameness as a result of a pathological development in the steeper foot

A double blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients

Antidepressant effects of mirtazapine and imipramine were compared in a randomized, double blind, fixed blood-level study with in-patients in a single centre. Patients with a DSM-III-R diagnosis of major depression and a Hamilton (17-item) score of ≤ 18 were selected. After a drug-free and a placebo-washout period of 7 days in total, 107 patients still fulfilling the HRSD criterion of ≤ 18, started on active treatment. The dose was adjusted to a predefined fixed blood level to avoid suboptimal dosing of imipramine. Concomitant psychotropic medication was administered only in a few cases because of intolerable anxiety or intolerable psychotic symptoms. Eight patients dropped out and two were excluded from analyses because of non-compliance; 97 completed the study. According to the main response criterion (50% or more reduction on the HRSD score) 11/51 (21.6%) patients responded on mirtazapine and 23/46 (50%) on imipramine after 4 weeks' treatment on the predefined blood level. Such a dramatic difference in efficacy between antidepressants has not often been reported before. The selection of (severely ill) in-patients, including those with suicidal or psychotic features, may have significance in this respect. Optimization of treatment with the reference drug imipramine through blood level control, exclusion of non-compliance for both drugs, exclusion of most concomitant medication and a low drop-out rate may also have contributed. It is concluded that imipramine is superior to mirtazapine in the patient population studied