Theo F. Meert

Survey on the pharmacodynamics of the new antipsychotic risperidone

This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT2 receptor blockade as shown by displacement of radioligand binding (Ki: 0.16 nM), activity on isolated tissues (EC50:0.5 nM), and antagonism of peripherally (ED50: 0.0011 mg/kg) and centrally (ED50:0.014 mg/kg) acting 5-HT2 receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT2 receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D2 receptor antagonist as indicated by displacement of radioligand binding (Ki: 1.4 nM), activity in isolated striatal slices (IC50: 0.89 nM), and antagonism of peripherally (ED50: 0.0057 mg/kg in dogs) and centrally acting D2 receptor agonists (ED50: 0.056–0.15 mg/kg in rats). Risperidone shows all effects common to D2 antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4–10 times less potent than haloperidol as a central D2 antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT2 antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D2 antagonism; synergism of combined 5-HT2/D2 antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D2 receptors and at D2 receptors from various rat brain regions. The binding affinity for D4 and D3 receptors is 5 and 9 times weaker, respectively, than for D2 receptors; interaction with D1 receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H1 and α-adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D2 antagonist with predominant 5HT2 antagonistic activity and optimal pharmacokinetic properties.

Further evidence validating adjuvant arthritis as an experimental model of chronic pain in the rat

The experiments described here were aimed at further validating adjuvant arthritis as an animal model of chronic pain. It was found that the relative oral intake of a 0.008 mg/ml solution of fentanyl was higher in arthritic than in normal control rats; this difference was predicted by the notion that the analgesic effect of a substance may reinforce its intake in animals exposed to pain, more so than in normal pain-free animals. It was also found that body weight decreases and that vocalizations of aggregated rats increase as a result of the challenge; these effects suggest that the vegetative signs and the behavioral irritability which are characteristic of chronic pain in humans, also occur in arthritic animals. The pain which thus seems to be associated with adjuvant arthritis was estimated to have its onset on days 10-11, to peak on days 18-21, and to terminate on days 35-40 after inoculation with Mycobacterium butyricum.

Behavioral and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in rat

The newly synthesized compound and putative 5-HT2 antagonist ritanserin, but not the structurally related compound R 56413, resembles pirenperone in that it acts as a pure antagonist in an LSD-saline drug discrimination assay in the rat. Ritanserin exceeded pirenperone in terms of behavioral specificity; the lowest effective dose of ritanserin in antagonizing LSD was one order of magnitude higher than that of pirenperone, but the compound depressed rate of operant responding only at doses that were about 1000-fold higher than those at which pirenperone was effective. Ritanserin exerted effects in an open field test which were reminiscent of anxiolytic drug activity in the rat; its effects were greater than those of pirenperone, R 56413 and the benzodiazepines chlordiazepoxide and diazepam. The results of experiments on antagonism of 5-HT-induced hypothermia and of the 5-HTP-induced headtwitch response fail to support the possibility that the putative anxiolytic effects of ritanserin in the rat can be ascribed simply to a pharmacologically defined action at 5-HT receptors.

Potentiation of the Analgesic Properties of Fentanyl-like Opioids With Alpha(2)-adrenoceptor Agonists in Rats

Background:Data on the analgesic properties of α2 agonists and their interactions with opioids are conflicting. Experiments were conducted in rats to evaluate whether various available α2 agonists can potentiate the analgesic properties of opioids and to determine the route of administration needed for optimal interaction. Methods:The tail-withdrawal reaction test was used as an analgesia assay. In separate experiments, the interactions between systemic (subcutaneous, intravenous, and intraperitoneal) and spinally (epidural and intrathecal) administered α2 agonists and opioids were evaluated. The antagonism of medetomidine plus fentanyl with naloxone and /or idazoxan also was studied. Results:All α2 agonists tested, when injected subcutaneously with fentanyl, potentiated the opioid-induced analgesia. In terms of a reduction of the amount of fentanyl needed to produce a deep surgical analgesia (tail-withdrawal reaction latency 2≥10s) over more than 2 h, the relative order of potency of the α2 agonists tested was: medetomidine > dexmedetomidine > xylazine>clonidine > detomidine. For some of these α2 agonists there was a biphasic effect; at the larger doses tested, a reduction in the fentanyl potentiation was present. The potentiation of the opioid activity with α2 agonists was also demonstrated in terms of a longer duration of analgesia after combined treatment with fixed doses of opioids. The interaction between the α2 agonists and the opioids remained present when a more profound criterion of analgesia (tail-withdrawal reaction latency ≥ 30 s) was used. Furthermore, the interactions between the α2 agonists tested and fentanyl or sufentanil appeared to be independent of the route of administration. Potentiations were observed after simultaneous subcutaneous injections of both groups of compounds, after the combination of intraperitoneal (α2 agonist) plus subcutaneous (opioid), intravenous (α2 agonist) plus epidural (opioid) and simultaneous epidural or intrathecal administrations. With regard to antagonism of the analgesic activity of combined treatment with α2 agonists plus opioids, naloxone provided total antagonism, whereas the α2 antagonist idazoxan overcame only the α2 agonist-induced potentiation of fentanyl. Conclusions:The tested α2 agonists can potentiate the analgesic properties of opioids, but they have no intrinsic antinociceptive effects on spinal reflexes on their own. The potentiating activities of the α2 agonists could be measured both in terms of a reduction of the amount of opioid needed to reach a particular level of analgesia and in terms of a longer duration of analgesia with a fixed dose of the opioid. The potentiations were observed with various α2 agonists and opioids and appeared independent of the routes of administration.

Systemic Immune Activation Leads to Neuroinflammation and Sickness Behavior in Mice

Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS) is commonly used to study inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice and increased immunoreactivity against the microglial marker ionized calcium-binding adapter molecule 1 in the dentate gyrus of wild-type mice. Furthermore, LPS treatment caused a strong but transient increase in cytokine levels in the serum and brain. In addition to studying LPS-induced neuroinflammation, we tested whether sickness could be separated from depressive-like behavior by evaluating LPS-treated mice in a panel of behavioral paradigms. Our behavioral data indicate that systemic LPS administration caused sickness and mild depressive-like behavior. However, due to the overlapping time course and mild effects on depression-related behavior per se, it was not possible to separate sickness from depressive-like behavior in the present rodent model.

Novel Role for Vascular Endothelial Growth Factor (VEGF) Receptor-1 and Its Ligand VEGF-B in Motor Neuron Degeneration

Although vascular endothelial growth factor-B (VEGF-B) is a homolog of the angiogenic factor VEGF, it has only minimal angiogenic activity, raising the question of whether this factor has other (more relevant) biological properties. Intrigued by the possibility that VEGF family members affect neuronal cells, we explored whether VEGF-B might have a role in the nervous system. Here, we document that the 60 kDa VEGF-B isoform, VEGF-B186, is a neuroprotective factor. VEGF-B186 protected cultured primary motor neurons against degeneration. Mice lacking VEGF-B also developed a more severe form of motor neuron degeneration when intercrossed with mutant SOD1 mice. The in vitro and in vivo effects of VEGF-B186 were dependent on the tyrosine kinase activities of its receptor, Flt1, in motor neurons. When delivered intracerebroventricularly, VEGF-B186 prolonged the survival of mutant SOD1 rats. Compared with a similar dose of VEGF, VEGF-B186 was safer and did not cause vessel growth or blood–brain barrier leakiness. The neuroprotective activity of VEGF-B, in combination with its negligible angiogenic/permeability activity, offers attractive opportunities for the treatment of neurodegenerative diseases.

A preclinical comparison between different opioids: antinociceptive versus adverse effects

Reduced side-effect liability of opioids may enhance the patients quality of life and decrease the incidence of opioid-insensitive pain. Literature offers few comparative data between different opioids at equianalgesic doses. Therefore morphine, fentanyl, buprenorphine, codeine, hydrocodone and oxycodone were compared for analgesic properties and side-effect profiles in rats. Analgesic efficacy was analysed using a tail withdrawal test for acute thermal nociception, a formalin test for chemically induced inflammatory pain and a von Frey test for mechanical hypersensitivity. For side-effect profiling inhibition of gastrointestinal activity was evaluated in a charcoal and ricinus oil test, arterial PCO(2) was determined for measuring respiratory depression, the discriminative stimulus properties linked to the narcotic cue were assessed using a drug discrimination learning test, and motor coordination was tested through rotarod performance. ED(50)s for the occurrence of side-effects were compared to ED(50)s in behavioural pain tests. Fentanyl had a strong analgesic potency and, compared to other opioids, an acceptable side-effect profiling at analgesic ED(50)s. Also consistent was the ceiling effect of buprenorphine implying an increased safety margin for side-effects, but a decreased analgesic efficacy. Differences between opioids as observed in this study can have important indications for their use in acute as well as in the onset of chronic treatments.

Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat

The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to 10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, whereas the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neurons cell body being exposed to high and persistent levels of paclitaxel.

Making sense of big data in health research: Towards an EU action plan

Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of “big data” for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health and healthcare for all Europeans.

The shock probe conflict procedure. A new assay responsive to benzodiazepines, barbiturates and related compounds

Rats that are placed in a novel environment containing a probe will explore the environment and the probe. Exploration of the probe is reduced when the probe is electrified. We here report that chlordiazepoxide blocks this inhibition, and have determined some of the pharmacological features of this new experimental procedure. The procedure appears to be sensitive to the effects of several benzodiazepines, barbiturates, and related compounds. Limited activity was observed with most 5-HT antagonists, ritanserin, an anticholinergic, a β-adrenergic blocker and a neuroleptic. Of the antidepressants, only imipramine had some limited activity. Inactive compounds in this procedure include benzodiazepine antagonists, buspirone, convulsants, opiates, an opiate antagonist, stimulants, a putative DA agonist and antagonist, histamine antagonists, a cholinomimetic, anticholinergics, a NE antagonist, α2 agonists, an α2 antagonist, MAO inhibitors, 5-HTP and LSD.