BackgroundChronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain.MethodNeuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively.ResultsIn vivo microdialysis experiments showed that each MRI increased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3mg/kg) reversed the full repertoire of OXA-induced neuropathic hypersensitivity. NS18283 (10mg/kg) reversed OXA-induced mechano-hypersensitivity and cold allodynia. Venlafaxine (16mg/kg) and escitalopram (4mg/kg) only reversed cold allodynia and mechano-hypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice.ConclusionsAcute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation.

L’antibiothérapie est la pierre angulaire du traitement du sepsis d’origine bactérienne. Ce traitement anti-infectieux doit être actif sur les germes et être mis en place sans délai. En sus du spectre d’activité antibactérienne, la posologie (dose et fréquence d’administration) doit être optimale pour assurer le maximum d’efficacité. Comme tous les médicaments, les antibiotiques sont soumis à différentes voies métaboliques d’élimination, notamment rénale. L’insuffisance rénale expose au surdosage de certains antibiotiques et donc à une toxicité médicamenteuse. Les patients en choc septique sont à risque de développer une insuffisance rénale sévère nécessitant l’épuration extrarénale (EER). L’EER remplace partiellement la fonction d’élimination médicamenteuse rénale. Lors de l’administration d’un antibiotique, l’impact pharmacocinétique de l’EER doit être correctement pris en compte pour éviter un surdosage toxique ou sous-dosage à l’origine d’un échec thérapeutique. Les modifications pharmacocinétiques d’une antibiothérapie chez un patient en réanimation dépendent du couple antibiotique-dialyseur (poids moléculaire, liaison aux protéines, caractéristiques moléculaires physicochimiques et ioniques, coefficient de partage ou de sieving), du patient (volume de distribution, différentes voies d’élimination fonctionnelles) et des méthodes d’EER (diffusion, convection, méthode continue, intermittente). Des modèles mathématiques calculés à partir des caractéristiques physicochimiques (notamment le coefficient de sieving) de l’antibiotique et des caractéristiques de l’EER (notamment les débits sanguins et de dialysat) permettent une adaptation des posologies de l’antibiothérapie lorsque des dosages sériques sont indisponibles. Schématiquement, au cours de l’EER, par rapport au traitement standard, l’adaptation de la posologie des antibiotiques concentration-dépendant repose sur l’espacement de l’intervalle de temps entre les administrations, sans modification de dose, et celle des antibiotiques temps-dépendant sur la réduction de la dose sans modification des intervalles d’administration. En phase aiguë d’un choc septique bactérien, la priorité est à l’efficacité, et dans le doute un surdosage est préférable à un sous-dosage. Une infection non traitée est à l’origine d’une plus grande mortalité que les effets toxiques d’une antibiothérapie.

Antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRI) act as indirect agonists of serotonin (5-HT) receptors. Although these drugs produce a rapid blockade of serotonin transporters (SERTs) in vitro, several weeks of treatment are necessary to observe clinical benefits. This paradox has not been solved yet. Recent studies have identified modifications of intracellular signaling proteins and target genes that could contribute to antidepressant-like activity of SSRI (e.g., increases in neurogenesis and BDNF protein levels), and may explain, at least in part, their long delay of action. Although these data suggest a positive regulation of 5-HT on the expression of the gene coding for BDNF, the reciprocal effects of BDNF on brain 5-HT neurotransmission remains poorly documented. To study the impact of BDNF on serotonergic activity, a dual experimental strategy was used to analyze neurochemical and behavioral consequences of its decrease (strategy 1) or increase (strategy 2) in the brain of adult male mice. (1) In heterozygous BDNF+/− mice in which brain BDNF protein levels were decreased by half, an enhancement of basal extracellular 5-HT levels (5-HText) that induced a down-regulation of SERT, i.e., a decrease in its capacity to reuptake 5-HT, was found in the hippocampus. In addition, the SSRI, paroxetine, failed to increase hippocampal 5-HText in BDNF+/− mice, while it produces robust effects in wild-type littermates. Thus, BDNF+/− mice can be viewed as an animal model of genetic resistance to serotonergic antidepressant drugs. (2) In wild-type BDNF+/+ mice, the effects of intra-hippocampal (vHi) injection of BDNF (100ng) in combination with a SSRI was examined by using intracerebral microdialysis and behavioral paradigms that predict an antidepressant- and anxiolytic-like activity of a molecule [the forced swim test (FST) and the open field paradigm (OF) respectively]. BDNF induced a rapid and transient increase in paroxetine response on 5-HText in the adult hippocampus, which was correlated with a potentiation of its antidepressant-like activity in the FST. The effects of BDNF were selectively blocked by K252a, an antagonist of its high-affinity TrkB receptor. Such a correlation between neurochemical and behavioral effects of [BDNF+SSRI] co-administration suggests that its antidepressant-like activity is linked to the activation of 5-HT neurotransmission in the adult hippocampus. BDNF also had a facilitatory effect on anxiety-like behavior in the OF test, and paroxetine prevented this anxiogenesis. What was the mechanism by which BDNF exerted these latter effects? Surprisingly, by using zero net flux method of quantitative microdialysis in vivo, we found that an intra-hippocampal BDNF injection in wild-type mice decreased the functional activity of SERT as observed in BDNF+/− mice. However, the decreased capacity of SERT to reuptake 5-HT was not associated to an increase in basal 5-HText in the hippocampus of WT mice. Interestingly, using in situ hybridization experiments indicated that TrkB receptor mRNA was expressed in the hippocampus and dorsal raphe nucleus in adult mice suggesting that the neurochemical and behavioral effects of intra-hippocampal BDNF injection can mobilize both pre- and post-synaptic elements of the brain 5-HT neurotransmission. Taken together, these set of experiments unveiled a relative opposition of neurochemical and behavioral responses following either a decrease (in BDNF+/− mutant mice) or an increase in brain BDNF levels (bilateral intra-hippocampal injection) in adult mice. In view of developing new antidepressant drug strategy, a poly-therapy combining BDNF with a chronic SSRI treatment could thus improve the efficacy of current medications.

Permeability-glycoprotein (Pgp) is a drug transporter responsible for the efflux of xenobiotics out of cells that influence the pharmacokinetics of numerous drugs. However, the role of this transporter in drug–drug interactions is still poorly studied even though a lot of P-glycoprotein substrates and P-glycoprotein inhibitors are identified among drugs of standard usage. On one hand, Pgp is distributed within a lot of organs and tissues implicated in the absorption or excretion of xenobiotics, and drug–drug interactions with this protein may increase the bioavailability of simultaneously administered active drugs. On the other hand, Pgp is linked to the integrity of blood–tissue barriers, such as the blood–brain barrier or placenta, and a partial blockage of Pgp could be responsible for a new drug distribution in the organism with possible increase of drug rates in organs behind these barriers. Therefore, concomitant administration of substrates and Pgp inhibitors would modify drug pharmacokinetics by increasing bioavailability and organ uptake, leading to more adverse drug reactions and toxicities. Consequently, the identification and comprehension of these drug–drug interactions remain important keys to risk assessment.

A method was developed and validated for the analysis of R(-)-apomorphine, (R-)-apocodeine and R(-)-norapomorphine in human plasma and urine with N-propylnorapomorphine as internal standard using gas chromatography/mass spectrometry (GC/MS) and single-ion monitoring after a single liquid-liquid extraction and silylation of compounds. The quantification limits were 1 ng/ml for apomorphine and apocodeine and 25 ng/ml for norapomorphine. Calibration curves were linear, within the range 1-100 ng/ml. Variation in intraday and interday precision was below 10%. This method was applied to study apomorphine bioavailability in nine patients with Parkinson's disease before and after coadministration of a catechol-O-methyl transferase inhibitor.

Vincristine (VCT) is a neurotoxic agent and also a substrate of multidrug resistance (MDR) transporters such as P-glycoprotein (P-gp) and MDR-associated proteins 1 and 2 (MRP1 and MRP2). These proteins are expressed in the central and peripheral nervous systems (CNS and PNS) and normally protect these structures against the harmful effects of VCT. The aim of this study was to elucidate the paradoxical relation between the MDR transporters and the VCT neurotoxicity. With a validated rat model of VCT-induced neuropathy, (1) the expressions of mdr1a (P-gp), mdr1b (P-gp), mrp1 (MRP1), and mrp2 (MRP2) genes were assessed by quantitative real-time polymerase chain reaction, and (2) the transporter activity was monitored using a radioactive tracer, Tc-99m-sestamibi, in the CNS and PNS. The results showed higher expression of mdr1a and mdr1b genes (x3 and x35, respectively) in the brain than in the spinal ganglia in both control and treated animals. Transporter activity was higher (x 10) in the CNS than in the PNS. Hence, P-gp protection may be lower in the PNS than in the CNS, and this may be responsible for the peripheral neurotoxicity of P-gp substrates. VCT treatment increased expression of the mdr1a gene in the CNS and PNS (both x 1.7), mrp1 gene in the PNS (x1.7), and transporter activity in both the CNS and the PNS (x4 and x8, respectively). This transporter. induction may induce adverse effects when analgesic drugs are administered to treat neuropathic pain.

To quantify gamma-hydroxybutyrate (GHB) and its physiological metabolites, gamma-aminobutyric acid (GABA), 1,4-butanediol (1,4-BD), and gamma-butyrolactone (GBL) in various animal tissues (kidney, muscle, heart, liver, blood, brain cortex, thalamus, hypothalamus, hippocampus, or pons), an original gas chromatographic/mass spectrometric method with a automated solid-phase extraction by Oasis MCX cartridges on a Gilson Aspec Xli was developed. Using such apparatus allowed the limit of detection (LOD) of target compounds to be significantly lowered (LOD: 0.027, 0.025, and 5.7 microg/mL for GHB, 1,4-BD, and GABA, respectively, in 200 microL or microg of sample). After validation of each analytical step, the satisfactory performances of the apparatus in conjunction with the rapidity and ease of the extraction step make it suitable for simultaneous assay of GHB, 1,4-BD, GBL, and GABA. The method was used to test the correlation between GHB levels in tissues obtained at different times after death of male Sprague-Dawley rats and the postmortem interval. Preliminary results show a linear increase of GHB levels in relation to time of death in thoracic blood and central nervous system of animals kept at 15 and 20 degrees C.

L'oxaliplatine est un médicament anticancéreux connu pour induire rapidement des neuropathies douloureuses spécifiques. En effet, le froid est un facteur déclenchant ou aggravant des sensations douloureuses des patients, altérant de manière importante leur qualité de vie. Afin de prévenir et de traiter ces symptômes, il est important de développer des modèles animaux reproduisant ceux-ci. Les animaux (rats mâles Sprague-Dawley 160- 180g) reçoivent l'oxaliplatine (DebioClinic®) (0 ; 0,12 ; 0,24 ; 0,47, 1 ; 2 ; 4 mg/kg i.v.) deux fois par semaine pendant cinq semaines. Les test comportementaux moteurs (actimétrie, Grip-Strength) et sensitifs (Test de Randall et Selitto, Test des filaments de Von Frey, Test d'immersion de la queue à différentes températures) sont effectués avant chaque injection. Lors des injections, nous avons observé une bonne conservation de l'état général des animaux avec absence de différences de gains de poids d'avec les animaux contrôles. L'oxaliplatine provoque dès la première injection à la plus faible dose une hyperalgie et une allodynie thermique au froid, avec une baisse maximale de − 89 % des seuils nociceptifs à la 9e injection des trois doses les plus faibles. À 42 et 46°C, les symptômes sont aussi présents mais moins intenses (baisse de − 64 % à J + 16). On observe aussi une hyperalgie et une allodynie mécanique. Ces résultats montrent que l'oxaliplatine induit chez l'animal comme chez l'homme l'apparition d'importants symptômes douloureux liés à la température dès la première injection et persistant en chronique. La validation complète de ce modèle doit permettre d'étudier de manière précise la physiopathologie de ces troubles.

We report the assessment of motor and sensory behaviors using an electrophysiologic and an histologic approach, in a rat model of cisplatin peripheral neuropathy. Cisplatin was injected intraperitoneally one (3 mg/ kg), two (2 mg/kg), or three (1 mg/kg) times a week up to a cumulative dose of 15 or 20 mg/kg. With regard to nociceptive signs, we observed mechanical and thermal (cold stimuli) hyperalgesia and allodynia associated with minor motor disorders for the 3 mg/kg dose. Peripheral nerve conduction velocities were decreased in the cisplatin-(3 mg/kg) treated group. In addition, the histologic approach revealed that large axons were more frequently affected than the small ones, and nonmyelinated axons were unaffected. However, even in the most severe cases, myelin sheaths remained within normal limits. This animal model of nociceptive neuropathy would be suitable to study the pathophysiologic mechanisms of neuropathic pain and to test potential neuroprotective agents.

Using doses close to those used clinically, we have developed an animal model of vincristine-induced nociceptive sensory neuropathy after repeated intravenous injection in male Sprague–Dawley rats. In order to validate the model, three different doses (50, 100 and 150μg/kg) of vincristine were injected every 2nd day until five injections had been given. The sensory behavioural assessment revealed mechanical hyperalgesia and allodynia associated with cold thermal hyperalgesia and allodynia. With regard to electrophysiological evaluation, we observed a decrease in the nerve conduction velocity in the highest dose group. Morphological studies revealed few degenerated fibers in the sciatic nerve and many degenerated myelinated axons in the fine nerve fibers of the subcutaneous paw tissue. Finally, to develop an animal model, we chose the 150μg/kg dose because of the good general clinical status of the rats without motor function changes associated with severe sensation disorders like hyperalgesia and allodynia. This model of vincristine-induced painful neuropathy will be used to explore physiopathological mechanisms implied in the genesis of neuropathic pain and also to test new analgesic and neuroprotective drugs.

Dimethylsulfoxide (DMSO) is a solvent used to dissolve hydrophobic drugs. Recent studies have demonstrated that repeated administration of DMSO induces significant disorders of the peripheral nervous system. To address this issue, we have studied the behavioural effects of repeated intraperitoneal injections of various concentrations of DMSO (1.8-3.6-7.2%) in male Sprague-Dawley rats. Behavioural effects were assessed with a commonly used battery of sensory and motor tests. The motor tests used were actimeter and grip strength test. Sensory test used noxious and non-noxious mechanical (paw pressure test and von Frey hairs test) and thermal (plantar test and tail immersion test) stimuli. Clinical status of the animals was good throughout the experiment and no motor deficits were observed. Nevertheless, sensory assessment displayed a mechanical allodynia of short duration.

The possibility that chronicle oral ingestion of fluoride-rich water could modify peripheral pain sensitivity was studied in two strains of adult rats, Sprague-Dawley and Lou/C rats. Sodium fluoride was given orally in water to male Sprague-Dawley (75 and 150 ppm) and Lou rats (150 ppm) for 15 and 27 weeks, respectively. Using classical behavioural evaluation methods of pain symptoms, only slight tendencies to a thermal hyperalgia and a mechanical allodynia were observed in Sprague-Dawley rats.