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Types of studies: double-blind randomized controlled trials (RCTs) or quasi-RCTsTypes of participants: adults with a diagnosis of probable or definite ALSTypes of interventions: gabapentin, baclofen, or other GABA modulators compared with placebo, no treatment, or each otherPrimary outcome: survival at one year from study enrollmentSecondary outcomes: individual rate of decline of maximum voluntary isometric contraction (MVIC), expressed as arm megascore; rate of decline of per cent predicted forced vital capacity (FVC); rate of decline of ALS Functional Rating Scale (ALSFRS); health-related quality of life; survival evaluated by pooling hazards; and adverse events DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.
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Mechanisms other than acid reflux are involved in some of the symptoms of gastro-oesophageal reflux disease. Controlled outcome studies are needed to clarify their roles and the indications for antireflux procedures in patients with persistent symptoms whilst 'on' a proton pump inhibitor.
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Forty-three patients with severe traumatic brain injuries who were previously implanted with an intrathecal baclofen pump were included to be evaluated in the long-term with the Coma Recovery Scale-Revised. The Barthel Index, the Glasgow Outcome Scale, the Ashworth scale, the scores of hypertonic attacks, of sweating episodes and of voluntary motor responses were used to describe functional abilities and residual impairments. A retrospective analysis highlighted patients' characteristics at admission, before surgery and their complications.
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The GABA(B) receptor was the first heteromeric G-protein coupled receptor (GPCR) identified. Indeed, both GABA(B1) and GABA(B2) subunits appear necessary to get a functional GABA(B) receptor. Soon after the cloning of both subunits, it was demonstrated that GABA(B2) was required for GABA(B1) to reach the cell surface. However, even a mutated GABA(B1) able to reach the cell surface is not functional alone despite its ability to bind GABA(B) ligands. This clearly demonstrated that GABA(B2) is not only required for the correct trafficking of GABA(B1) but also for the correct functioning of the receptor. In the present review article, we will summarize our actual knowledge of the specific role of each subunit in ligand recognition, intramolecular transduction, G-protein activation and allosteric modulation. We will show that the GABA(B) receptor is an heterodimer (not an hetero-oligomer), that agonists bind in GABA(B1), whereas GABA(B2) controls agonist affinity and is responsible for G-protein coupling. Finally, we will show that the recently identified positive allosteric modulator CGP7930 acts as a direct activator of the heptahelical domain of GABA(B2), being therefore the first GABA(B2) ligand identified so far.
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Irritability in children has a broad differential diagnosis, ranging from benign processes to life-threatening emergencies. In children with comorbid conditions and developmental delay, the diagnostic process becomes more challenging. This case report describes a developmentally delayed 14-year-old boy who presented with pain and crying caused by a malfunction of a surgically implanted baclofen pump. We describe recommendations concerning the diagnostic evaluation, medical management, and surgical repair.
Nerve growth factor (NGF) promotes the survival of embryonic sensory neurons and maintains the phenotypic characteristics of primary nociceptive neurons postnatally. NGF also contributes to nociceptor activation and hyperalgesia during inflammatory pain states. The purpose of this study was to determine whether NGF might have an additional pronociceptive action by interfering with opioid-mediated analgesia in primary nociceptive neurons. Sensory neurons were isolated from the dorsal root ganglia of weanling rats and kept in standard culture conditions either with or without exogenous NGF (50 ng/ml). Currents through voltage-gated calcium channels were recorded from individual neurons using the whole cell patch clamp technique with Ba(2+) as the charge carrier (I(Ba)). The micro-opioid agonist fentanyl (1 microM) and the GABA(B) agonist baclofen (50 microM) were used to test G protein-dependent inhibition of I(Ba). Fentanyl inhibited I(Ba) by an average of 38+/-4% in untreated cells vs. 25+/-2% in NGF-treated cells (P<0.01). NGF had no effect on I(Ba) current magnitude or kinetics. The NGF-induced attenuation of opioid action was observed as early as 4 h after exposure, but was not seen when NGF was applied by bath perfusion for up to 40 min, suggesting that the effect was not mediated by a rapid phosphorylation event. The effect of NGF was prevented by K-252a (100 nM), an inhibitor of TrkA autophosphorylation. Baclofen-induced inhibition of I(Ba), on the other hand, was not affected by NGF treatment, suggesting that NGF modulation of opioid-mediated inhibition occurred upstream from the G protein. This was supported by the finding that GTP-gamma-S, an agonist independent G protein activator, inhibited I(Ba) similarly in both untreated and NGF treated cells. The results show that NGF selectively attenuated opioid-mediated inhibition of I(Ba) via TrkA receptor activation, possibly by altering opioid receptor function.
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The effect of baclofen, a GABAB-agonist, was studied on both forced swimming-induced immobility and isoprenaline-induced enhancement of forced swimming-induced immobility in mice. (+/-) Baclofen (0.5 and 1 mg/kg), and (-) baclofen (0.5, 1 and 2 mg/kg) attenuated forced swimming-induced immobility. The effect of baclofen was not reversed by bicuculline, a GABAA-antagonist. Baclofen also reduced isoprenaline-induced enhancement of forced swimming-induced immobility. On concomitant administration of a subeffective dose of baclofen with a subeffective dose of propranolol, desipramine and amitriptyline, a potentiating effect was observed. These results are corroborative of our previous finding that GABAergic agents, particularly GABAB-receptors, play a role in the modulation of despair behavior in mice and in the action of antidepressant drugs. Baclofen (5 mg/kg) did not produce any significant effect on forced swimming-induced immobility, but reduced significantly the locomotor activity of the animals. Lower doses (0.5 and 1 mg/kg) of baclofen, which reduced the forced swimming-induced immobility, did not affect the locomotor activity. At higher and lower tissue concentrations of the drug, involvement of different receptor populations is suggested.
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In the mouse hot-plate test (50 degrees C), muscimol produced analgesia which was blocked by bicuculline but not by picrotoxin. Analgesia produced by baclofen was dose-dependent and stereoselective, but was not blocked by bicuculline, picrotoxin or naloxone. Morphine-induced analgesia was not altered by bicuculline. The inhibitors of GABA-transaminase, amino-oxyacetic acid, gamma-acetylenic GABA and gamma-vinyl GABA, produced analgesia which was much more prolonged than that observed with muscimol, baclofen or morphine. The analgesic action of these agents was not significantly altered by bicuculline. At a higher plate temperature (55 degrees C), GABA-transaminase inhibitors produced minimal analgesia but significantly enhanced the analgesic action of baclofen. gamma-Vinyl GABA markedly increased both the peak effect and the duration of analgesia but gamma-acetylenic GABA and amino-oxyacetic acid caused smaller increases. In the mouse hot-plate test, bicuculline-sensitive GABA receptors appear to mediate the analgesic action fo muscimol. Analgesia produced by baclofen, morphine and inhibitors of GABA-transaminase may involve another class of GABA receptors which are insensitive to bicuculline.
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gamma-Aminobutyric acid (GABA)-activated channels in embryonic (5-8 wk old) human dorsal root ganglion (DRG) neurons in dissociated culture were characterized by whole cell and single-channel techniques. All DRG neurons when held at negative holding membrane potentials displayed inward current to micromolar concentrations of GABA applied by pressure pulses from closely positioned micropipettes. The current was directly proportional to the concentration of GABA (EC50, 111 microM; Hill coefficient, 1.7). DRG neurons also responded to micromolar concentrations of pentobarbital and alphaxalone but not to cis-4-aminocrotonic acid (CACA), glycine, or taurine. Baclofen (100 microM) affected neither the holding currents nor K+ conductance (when patch pipettes were filled with 130 mM KCl) caused by depolarizing pulses. Whole cell GABA-currents were blocked by bicuculline, picrotoxin, and t-butylbicyclophosphorothionate (TBPS; all at 100 microM). The reversal potential of whole cell GABA-currents was close to the theoretical Cl- equilibrium potential, shifting with changes in intracellular Cl- concentration in a manner expected for Cl--selective channels. The whole cell I-V curve for GABA-induced currents demonstrated slight outward rectification with nearly symmetrical outside and inside Cl- concentrations. Spectral analysis of GABA-induced membrane current fluctuations showed that the kinetic components were best fitted by a triple Lorentzian function. The apparent elementary conductance for GABA-activated Cl- channels determined from the power spectra was 22.6 pS. Single-channel recordings from cell-attached patches with pipettes containing 10 microM GABA indicated that GABA-activated channels have a main and a subconductance level with values of 30 and 19 pS, respectively. Mean open and closed times of the channel were characterized by two or three exponential decay functions, suggesting two or three open channel states and two closed states. Single channels showed a lack of rectification. The actions of GABA on cultured human embryonic DRG neurons are mediated through the activation of GABAA receptors with properties corresponding to those found in the CNS of human and other mammalian species but differing from those of cultured human adult DRG neurons.
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This was a retrospective study of 6 children with intense chronic pain due to spasticity caused by cerebral palsy or genetic dystonia. Increasing doses of intrathecal baclofen in continuous perfusion through a tunneled catheter were tested.
Continuous infusion of intrathecal (IT) baclofen is a highly effective standard therapy for severe spasticity of spinal origin. By contrast, there is limited clinical experience regarding the use of IT baclofen in treating patients with dystonia, and little is known regarding the indications for treatment, efficacy, and safety of IT baclofen in this disorder.
1. Changes in the response properties of 106 ventral posterior medial (VPM) units were assessed after iontophoretic blockade of gamma-aminobutyric acid-A or -B (GABAA or GABAB) receptor-mediated inhibition using bicuculline methiodide (BIC) or 2-hydroxy-saclofen (2-OH-S), respectively. 2. The iontophoretic administration of either BIC or 2-OH-S did not alter significantly the average spontaneous firing rate of VPM neurons for current intensities between 40 and 80 nA. The presence of 10 mM 2-OH-S (60 nA) was effective in completely reversing the depressant effects of the selective GABAB receptor agonist, baclofen, on the spontaneous activity of VPM neurons. 3. The effect of BIC on whisker-evoked responses was a preferential enhancement in the responses elicited by the whisker giving rise to the highest probability response (center receptive field whisker or CRF). The effect of 2-OH-S (40-80 nA iontophoretic currents) was to increase the responsiveness of VPM neurons to the stimulation of whiskers in all parts of the receptive field (RF), although its influence was much more pronounced in the peripheral areas of the RF (surround receptive field whisker or SRF). This preferential enhancement of SRF-whisker responses after the blockade of GABAB receptor-mediated inhibition resulted in a 2.3-fold increase in the average RF size of VPM neurons; no statistically significant increases in the size of the RF were seen in the presence of BIC. 4. The primary influence of BIC and, to a lesser degree, 2-OH-S was to prolong the response duration of VPM neurons to CRF whisker stimulation. Under our recording conditions, approximately 25% of VPM neurons in normal animals responded with sustained discharges. In the presence of BIC and 2-OH-S, the percent of VPM units that could be classified as tonically responding increased to 82% and 67%, respectively. 5. The proportion of VPM neurons that was selective to the deflection of whiskers in a particular direction (87%) was not altered in the presence of BIC or 2-OH-S. 6. BIC was effective in antagonizing GABA-mediated inhibition within the first 40 ms of a stimulus; BIC was completely ineffective in reversing a late suppression seen between 80 and 140 ms. In contrast, no statistically significant changes in the initial GABA-mediated inhibition were seen in the presence of 2-OH-S, but 2-OH-S was partially effective in antagonizing the late suppression of responses in VPM neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
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Gamma-hydroxybutyrate (GHB) is both a therapeutic agent and a recreative drug. It has sedative, anxiolytic and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral GABAergic and dopaminergic activities, but the serotonergic system might also be involved. In this study, we examine the effects of pharmacological doses of GHB on the serotonergic activity in rat brain. Administration of 4.0 mmol/kg i.p. GHB to rats induces an accumulation of tryptophan and 5-HIAA (5-hydroxyindole acetic acid) in the frontal cortex, striatum and hippocampus without causing significant change in the tissue serotonin content. In the extracellular space, GHB induced a slight decrease in serotonin release. The tryptophan and 5-HIAA accumulation induced by GHB is mimicked by the GHB receptor agonist para-chlorophenyl-transhydroxycrotonate (NCS-356) and blocked by NCS-382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol-4-ylidene acetic acid) a selective GHB receptor antagonist. GHB induces the accumulation of either a derivative of or [3H]-tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood-brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. Some of the effect of GHB could be reproduced by baclofen and reduced by the GABAB antagonist CGP 35348. Taken together, these results indicate that the GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration.