bluuebunny/crossref_metadata_2025 huggingface dataset:
A Combination of Gabapentin and Morphine Mediates Enhanced Inhibitory Effects on Dorsal Horn Neuronal Responses in a Rat Model of Neuropathy
Authors: Matthews Elizabeth A. , Dickenson Anthony H.
Published: August 2004

Background

Peripheral nerve damage can result in severe, long-lasting pain accompanied by sensory deficits. This neuropathic pain remains a clinical problem, and effective morphine analgesia is often limited by intolerable side effects. The antiepileptic gabapentin has recently emerged as an alternative chronic pain treatment. Improved management of the diverse symptoms and mechanisms of neuropathic pain may arise from combination therapy, based on multiple pharmacologic targets and low drug doses.

Methods

The authors used the Kim and Chung rodent model of neuropathy to induce mechanical and cold allodynia in the ipsilateral hind paw. In vivo electrophysiologic techniques were subsequently used to record evoked dorsal horn neuronal responses in which the effects of systemic morphine and gabapentin were investigated, both individually and in combination.

Results

Morphine (1 and 4 mg/kg) inhibited neuronal responses of control rats but not after neuropathy. Gabapentin (10 and 20 mg/kg) inhibited neuronal responses in nerve injured rats and to a lesser extent in sham rats but not in naive rats. In the presence of gabapentin (ineffective low dose of 10 mg/kg), morphine (1 and 3 mg/kg) mediated significant inhibitory effects in all experimental groups, with the greatest inhibitions observed in spinal nerve-ligated and sham-operated rats. After neuropathy, inhibitions mediated by morphine were significantly increased in the presence of gabapentin compared with morphine alone.

Conclusions

After spinal nerve ligation, the inhibitory effects of systemic morphine on evoked dorsal horn neuronal responses are reduced compared with control, whereas the effectiveness of systemic gabapentin is enhanced. In combination with low-dose gabapentin, significant improvement in the effectiveness of morphine is observed, which demonstrates a clinical potential for the use of morphine and gabapentin combinational treatment for neuropathic pain.
Ketamine Inhibits Sodium Currents in Identified Cardiac Parasympathetic Neurons in Nucleus Ambiguus
Authors: Irnaten Mustapha , Wang Jijiang , Chang Kyoung S. K. , Andresen Michael C. , Mendelowitz David
Published: August 2004

Background

Ketamine increases both blood pressure and heart rate, effects commonly thought of as sympathoexcitatory. The authors investigated the possibility that ketamine increases heart rate by inhibiting the central cardiac parasympathetic mechanisms.

Methods

We used a novel in vitro approach to study the effect of ketamine on the identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the nucleus ambiguus were retrogradely prelabeled with the fluorescent tracer by placing rhodamine into the pericardial sac. Dye-labeled neurons were visually identified for patch clamp recording, and ketamine effects on isolated potassium (K+) and sodium (Na+) currents were studied.

Results

Cardiac nucleus ambiguus neurons (n = 14) were inherently silent, but depolarization evoked sustained action potential trains with little delay or adaptation. Ketamine (10 microm) reduced this response but had no effect on the voltage threshold for action potentials (n = 14; P > 0.05). The current-voltage relations for the transient K+ current and the delayed rectified K+ current (n = 5) were unaltered by ketamine (10 mum-1 mm). Ketamine depressed the total Na+ current dose-dependently (10 microm-1 mm). In addition, ketamine shifted the Na+ current inactivation curves to more negative potentials, thus suggesting the enhancement of the Na+ channel inactivation (P < 0.05; n = 7). In the presence of Cd2+, ketamine (10 mum) continued to inhibit voltage-gated Na+ currents, which recovered completely within 10 min.

Conclusions

Ketamine inhibits Na+ but not K+ channel function in brainstem parasympathetic cardiac neurons, and such actions may mediate the decrease in parasympathetic cardiac activity and increase in heart rate that occurs with ketamine.
Extracellular Magnesium Ion Modifies the Actions of Volatile Anesthetics in Area CA1 of Rat Hippocampus In Vitro
Authors: Sasaki Rika , Hirota Koki , Roth Sheldon H. , Yamazaki Mitsuaki
Published: August 2004

Background

Magnesium ion (Mg2+) is involved in important processes as modulation of ion channels, receptors, neurotransmitter release, and cell excitability in the central nervous system. Although extracellular Mg2+ concentration ([Mg2+]o) can be altered during general anesthesia, there has been no evidence for [Mg2+]o-dependent modification of anesthetic actions on neural excitability in central nervous system preparations. The purpose of current study was to determine whether the effects of volatile anesthetics are [Mg2+]o-dependent in mammalian central nervous system.

Methods

Extracellular electrophysiologic recordings from CA1 neurons in rat hippocampal slices were used to investigate the effects of [Mg2+]o and anesthetics on population spike amplitude and excitatory postsynaptic potential slope.

Results

The depression of population spike amplitudes and excitatory postsynaptic potential slopes by volatile anesthetics were significantly dependent on [Mg2+]o. The effects were attenuated in the presence of a constant [Mg2+]o/extracellular Ca2+ concentration ratio. However, neither N-methyl-d-aspartate receptor antagonists nor a non-N-methyl-d-aspartate receptor antagonist altered the [Mg2+]o-dependent anesthetic-induced depression of population spikes. Volatile anesthetics produced minimal effects on input-output (excitatory postsynaptic potential-population spike) relations or the threshold for population spike generation. The effects were not modified by changes in [Mg2+]o. In addition, the population spike amplitudes, elicited via antidromic (nonsynaptic) stimulation, were not influenced by [Mg2+]o in the presence of volatile anesthetics.

Conclusions

These results provide support that alteration of [Mg2+]o modifies the actions of volatile anesthetics on synaptic transmission and that the effects could be, at least in part, a result of presynaptic Ca2+ channel-related mechanisms.
Selective Synaptic Actions of Thiopental and Its Enantiomers
Authors: Dickinson Robert , M. de Sousa Sara L. , Lieb William R. , Franks Nicholas P.
Published: August 2004

Background

There is conflicting evidence concerning the extent to which the intravenous general anesthetic thiopental acts by enhancing inhibitory gamma-aminobutyric acid-mediated (GABAergic) synaptic transmission or by inhibiting excitatory glutamatergic transmission. Yet there are remarkably few studies on the effects of thiopental on functional synapses. In addition, the degree of stereoselectivity of thiopental acting at synapses has yet to be tested.

Methods

The actions of thiopental and its enantiomers on GABAergic and glutamatergic synapses were investigated using voltage clamp techniques on microisland cultures of rat hippocampal neurons, a preparation that avoids the confounding effects of complex neuronal networks.

Results

Racemic thiopental markedly enhanced the charge transfer at GABAergic synapses without significantly affecting the peak of the postsynaptic current. At a surgically relevant concentration (25 microm), charge transfer was increased by approximately 230%. However, even at twice this concentration there were no significant effects on glutamatergic postsynaptic currents. At GABAergic synapses, thiopental acted stereoselectively, with the S(-) enantiomer being approximately twice as effective as the R(+) enantiomer at enhancing charge transfer.

Conclusions

Thiopental stereoselectively enhances inhibitory GABAergic synaptic transmission in a way that reflects animal potencies, supporting the idea that this is a principal mode of action for this drug. The absence of any effect on glutamatergic synapses at surgically relevant concentrations suggests that the inhibition of these excitatory synapses is not an important factor in producing thiopental general anesthesia.
Preconditioning with Hyperbaric Oxygen and Hyperoxia Induces Tolerance against Spinal Cord Ischemia in Rabbits
Authors: Dong Hailong , Xiong Lize , Zhu Zhenghua , Chen Shaoyang , Hou Lichao , Sakabe Takefumi
Published: August 2004

Background

The aim of this study was to determine if the ischemic tolerance could be induced in the spinal cord by pretreatment with hyperbaric oxygen (HBO) and what components of HBO (hyperoxia, hyperbaricity, and combination of these two) were critical in the induction of tolerance against ischemic injury.

Methods

In experiment 1, 21 rabbits were randomly assigned to one of three groups (n = 7 each): animals in the control group received no HBO before spinal cord ischemia; animals in the HBO-1 and HBO-2 groups received HBO (2.5 atmosphere absolute [ATA], 100% O2) pretreatment 1 h/day for 3 and 5 days before ischemia, respectively. In experiment 2, 48 rabbits were randomly assigned to one of four groups (n = 12 each): the control group received no HBO (21% O2, 1 ATA, 1 h/day, 5 days) before spinal cord ischemia; the HB group received 1-h treatment in 21% O2 at 2.5 ATA each day for 5 days; the HO group received 1-h treatment in 100% oxygen at 1 ATA each day for 5 days; and the HBO group received HBO (2.5 ATA, 100% O2) treatment 1 h/day for 5 days. Twenty-four hours after the last treatment, spinal cord ischemia was induced by an infrarenal aorta clamping for 20 min. Forty-eight hours after reperfusion, hind-limb motor function and histopathology of the spinal cord were examined in a blinded fashion.

Results

In experiment 1, the neurologic outcome in the HBO-2 group was better than that of the control group (P = 0.004). The number of normal neurons in the anterior spinal cord in the HBO-2 group was more than that of the control group (P = 0.021). In experiment 2, the neurologic and histopathologic outcomes in the HBO group were better than that of the control group (P < 0.01). The histopathologic outcome in the HO group was better than that in the control group (P < 0.05).

Conclusions

Serial exposure to high oxygen tension induced ischemic tolerance in spinal cord of rabbits. Simple hyperbaricity (2.5 ATA, 21% O2) did not induce ischemic tolerance.
Isoproterenol Inhibits Transcription of Cardiac Cytokine Genes Induced by Reactive Oxygen Intermediates
Authors: Newman Walter H. , Castresana Manuel R. , Webb Jerry G. , Detmer Kristina , Wang Zhongbiao
Published: August 2004

Background

Cytokines such as tumor necrosis factor alpha (TNF-alpha) are produced by the myocardium in heart disease and might be stimulated by reactive oxygen. In some cell types, cyclic adenosine monophosphate (AMP) inhibits TNF-alpha production. The authors tested the hypothesis that stimulation of cardiac beta-adrenergic receptors would inhibit cytokine gene transcription induced by reactive oxygen.

Methods

Rat hearts were perfused with buffer containing hypoxanthine. Reactive oxygen intermediates were generated by infusion of xanthine oxidase. Myocardial mRNA encoding 11 cytokines was determined. TNF-alpha, interleukin-6, and cyclic AMP were measured in the coronary effluent.

Results

In control hearts, of the screened RNA, only mRNA encoding interleukin-1beta, -4, and -6 was detected. Stimulation with hypoxanthine-xanthine oxidase (HX-XO) induced detectable mRNA for TNF-alpha and interleukin-5 and increased mRNA band density for interleukin-1beta, -4, and -6. Simultaneous infusion of isoproterenol inhibited HX-XO-stimulated cytokine gene expression and caused release of cyclic AMP into the coronary effluent. In control hearts, TNF-alpha was not detected in the coronary effluent. After HX-XO administration, TNF-alpha was reliably detected at 60 min and interleukin-6 at 90 min. Simultaneous infusion of isoproterenol inhibited TNF-alpha and interleukin-6 release. Inclusion of propranolol in the perfusion buffer blocked the isoproterenol-induced inhibition of HX-XO-stimulated TNF-alpha release and release of cyclic AMP into the coronary effluent. In addition, elevating myocardial cyclic AMP with forskolin also blocked release of TNF-alpha stimulated by HX-XO. Finally, delaying infusion of isoproterenol until 30 min after HX-XO administration still suppressed release of TNF-alpha.

Conclusions

Reactive oxygen species activate cytokine gene transcription in the myocardium. The sympathetic nervous system, acting through beta-receptors to elevate myocardial cyclic AMP, regulates cardiac cytokine production by inhibition of transcription.
Accelerated Arteriolar Gas Embolism Reabsorption by an Exogenous Surfactant
Authors: Branger Annette B. , Eckmann David M.
Published: August 2004

Background

Cerebrovascular gas embolism can cause profound neurologic dysfunction, and there are few treatments. The authors tested the hypothesis that an exogenous surfactant can be delivered into the bloodstream to alter the air-blood interfacial mechanics of an intravascular gas embolism and produce bubble conformations, which favor more rapid bubble absorption.

Methods

Microbubbles of air were injected into the rat cremaster microcirculation after intravascular administration of either saline (control, n = 5) or Dow Corning Antifoam 1510US (surfactant, n = 5). Embolism dimensions and dynamics were directly observed after entrapment using intravital microscopy.

Results

To achieve embolization, the surfactant group required twice as many injections as did controls (3.2 +/- 1.3 vs. 1.6 +/- 0.9; P < 0.05). There was no difference in the initial lodging configuration between groups. After bubble entrapment, there was significantly more local vasoconstriction in the surfactant group (24.2% average decrease in diameter) than in controls (3.4%; P < 0.05). This was accompanied by a 92.7% bubble elongation in the surfactant group versus 8.2% in controls (P < 0.05). Embolism shape change was coupled with surfactant-enhanced breakup into multiple smaller bubbles, which reabsorbed nearly 30% more rapidly than did parent bubbles in the control group (P < 0.05).

Conclusions

Intravascular exogenous surfactant did not affect initial bubble conformation but dramatically increased bubble breakup and rate of reabsorption. This was evidenced by both the large shape change after entrapment and enhancement of bubble breakup in the surfactant group. These dynamic surfactant-induced changes increase the total embolism surface area and markedly accelerate bubble reabsorption.
Pharmacokinetics of Propofol Infusions in Critically Ill Neonates, Infants, and Children in an Intensive Care Unit
Authors: Rigby-Jones Ann E. , Nolan Judith A. , Priston Melanie J. , C. Wright Peter M. , Robert Sneyd J. , Wolf Andrew R.
Published: August 2004

Background

Propofol is a commonly used anesthetic induction agent in pediatric anesthesia that, until recently, was used with caution as an intravenous infusion agent for sedation in pediatric intensive care. Few data have described propofol kinetics in critically ill children.

Methods

Twenty-one critically ill ventilated children aged 1 week to 12 yr were sedated with 4-6 mg. kg(-1).h(-1) of 2% propofol for up to 28 h, combined with a constant morphine infusion. Whole blood concentration of propofol was measured at steady state and for 24 h after infusion using high-performance liquid chromatography.

Results

A propofol infusion rate of 4 mg. kg(-1).h(-1) achieved adequate sedation scores in 17 of 20 patients. In 2 patients the dose was reduced because of hypotension, and 1 patient was withdrawn from the study because of a increasing metabolic acidosis. Mixed-effects population models were fitted to the blood propofol concentration data. The pharmacokinetics were best described by a three-compartment model. Weight was a significant covariate for all structural model parameters; Cl, Q2, Q3, V1, and V2 were proportional to weight. Estimates for these parameters were 30.2, 16.0, and 13.3 ml. kg(-1).min(-1) and 0.584 and 1.36 l/kg, respectively. The volume of the remaining peripheral compartment, V3, had a constant component (103 l) plus an additional weight-related component (5.67 l/kg). Values for Cl were reduced (typically by 26%) in children who had undergone cardiac surgery.

Conclusions

Propofol kinetics are altered in very small babies and in children recovering from cardiac surgery. Increased peripheral distribution volume and reduced metabolic clearance following surgery causes prolonged elimination.
Both Local Anesthetics and Salbutamol Pretreatment Affect Reflex Bronchoconstriction in Volunteers with Asthma undergoing Awake Fiberoptic Intubation
Authors: Groeben Harald , Schlicht Markus , Stieglitz Sven , Pavlakovic Goran , Peters Jürgen
Published: August 2004

Background

Awake tracheal intubation may evoke reflex bronchoconstriction in asthmatics. Whether this effect is altered by the choice of the local anesthetic used or by pretreatment with a beta2-adrenoceptor agonist is unknown. Therefore, we assessed the effect of awake fiberoptic intubation after lidocaine or dyclonine inhalation with or without pretreatment with salbutamol on lung function in asthmatic volunteers.

Methods

Bronchial hyperreactivity was verified by an inhalational histamine challenge. On four different days in a randomized, double blind fashion the volunteers (n = 10) inhaled either dyclonine or lidocaine with or without salbutamol pretreatment. FEV1 was measured at baseline, following salbutamol or saline inhalation, after lidocaine or dyclonine inhalation, while intubated, and after extubation. Lidocaine and dyclonine plasma concentrations were also measured.

Statistics

Two-way ANOVA, post hoc tests with Bonferroni correction, results are presented as mean +/- SD.

Results

Neither lidocaine nor dyclonine inhalation changed FEV1 significantly from baseline compared with placebo inhalation (4.43 +/- 0.67 l vs. 4.29 +/- 0.72 l, and 4.53 +/- 0.63 l vs. 4.24 +/- 0.80 l, respectively). Salbutamol slightly but significantly increased FEV1 (4.45 +/- 0.76 l vs. 4.71 +/- 0.61 l, P = 0.0034, and 4.48 +/- 0.62 l vs. 4.71 +/- 0.61 l, P = 0.0121, respectively). Following awake intubation FEV1 significantly decreased under lidocaine topical anesthesia (4.29 +/- 0.72 l to 2.86 +/- 0.87 l) but decreased even more under dyclonine anesthesia (4.24 +/- 0.80 l to 2.20 +/- 0.67 l; P < 0.0001). While salbutamol pretreatment significantly attenuated the response to intubation, it did not eliminate the difference between the effects of lidocaine and dyclonine. Only minutes after extubation FEV1 was similar compared with baseline.

Conclusion

In asthmatics, awake fiberoptic intubation evokes a more than 50% decrease in FEV1 following dyclonine inhalation. Using lidocaine for topical anesthesia the decrease in FEV1 is significantly mitigated (35%) and can be even further attenuated by salbutamol pretreatment. Therefore, combined treatment with lidocaine and salbutamol can be recommended for awake intubation while the use of dyclonine, despite its excellent and longer lasting topical anesthesia, may be contraindicated in patients with bronchial hyperreactivity.
Effects of Bupivacaine on Mitochondrial Energy Metabolism in Heart of Rats following Exposure to Chronic Hypoxia
Authors: Nouette-Gaulain Karine , Forestier François , Malgat Monique , Marthan Roger , Mazat Jean-Pierre , Sztark François
Published: August 2004

Background

Adaptation to chronic exposure to hypoxia alters energy metabolism in the heart, particularly in the left ventricle, which undergoes a loss in oxidative capacity. Highly lipophilic local anesthetics interfere with mitochondrial energy metabolism. The purpose of this study was to compare the effects of bupivacaine on mitochondrial energy metabolism in heart of rats subjected to normoxic or hypoxic environments.

Methods

Male Wistar rats (n = 10) were subjected to hypobaric hypoxia (simulated altitude = 5,000 m, 380 mmHg) for 2 weeks. Control rats (n = 10) were maintained in an ambient normoxic environment. Mitochondrial metabolism (oxygen consumption and adenosine triphosphate synthesis) was assessed using saponin-skinned ventricular fibers. Bupivacaine (0-5 mM) was tested on both left and right ventricles of normoxic or hypoxic heart.

Results

In animals exposed to hypobaric hypoxia for 14 days, cardiac mass significantly increased, and the right-to-left ventricular ratio was approximately twofold (0.48 +/- 0.11 vs. 0.22 +/- 0.04, P < 0.05). Oxygen consumption and adenosine triphosphate synthesis were significantly lower in the hypoxic left ventricles but not in the right ones. The uncoupling effect of bupivacaine was more pronounced in the left ventricle from hypoxic heart than in the right ventricle; the bupivacaine-induced decrease in the adenosine triphosphate synthesis rate and in the adenosine triphosphate-to-oxygen ratio was significantly greater in the hypoxic left ventricle than in the normoxic one.

Conclusions

Chronic hypoxia impairs cardiac energy metabolism in left ventricles and enhances the depressant effects of bupivacaine on mitochondrial functions.
Desflurane Improves Neurologic Outcome after Low-flow Cardiopulmonary Bypass in Newborn Pigs
Authors: Loepke Andreas W. , Priestley Margaret A. , Schultz Steven E. , McCann John , Golden Jeffrey , Kurth C. Dean
Published: August 2004

Background

Despite improvements in neonatal heart surgery, neurologic complications continue to occur from low-flow cardiopulmonary bypass (LF-CPB) and deep hypothermic circulatory arrest (DHCA). Desflurane confers neuroprotection against ischemia at normothermia and for DHCA. This study compared neurologic outcome of a desflurane-based with a fentanyl-based anesthetic for LF-CPB.

Methods

Thirty piglets aged 1 week received either fentanyl-droperidol (F/D), desflurane 4.5% (Des4.5), or desflurane 9% (Des9) during surgical preparation and CPB. Arterial blood gases, glucose, heart rate, arterial pressure, brain temperature, and cerebral blood flow (laser Doppler flowmetry) were recorded. After CPB cooling (22 degrees C brain) using pH-stat strategy, LF-CPB was performed for 150 min followed by CPB rewarming, separation from CPB, and extubation. On postoperative day 2, functional and histologic outcomes were assessed.

Results

Cardiovascular variables were physiologically similar between groups before, during, and after LF-CPB. Cerebral blood flow during LF-CPB (13% of pre-CPB value) did not differ significantly between the groups. Functional disability was worse in F/D than in Des9 (P = 0.04) but not Des4.5 (P = 0.1). In neocortex, histopathologic damage was greater in F/D than in Des4.5 (P = 0.03) and Des9 (P = 0.009). In hippocampus, damage was worse in F/D than in Des9 (P = 0.01) but not Des4.5 (P = 0.08). The incidences of ventricular fibrillation during LF-CPB were 90, 60, and 10% for F/D, Des4.5 (P = 0.06), and Des9 (P = 0.0002), respectively.

Conclusions

Desflurane improved neurologic outcome following LF-CPB compared with F/D in piglets, indicated by less functional disability and less histologic damage, especially with Des9. Desflurane may have produced cardiac protection, suggested by a lower incidence of ventricular fibrillation.
Fetal and Maternal Effects of Phenylephrine and Ephedrine during Spinal Anesthesia for Cesarean Delivery
Authors: Cooper David W. , Carpenter Mark , Mowbray Paul , Desira William R. , Ryall David M. , Kokri Manmohan S.
Published: August 2004

Background

In our routine practice, we observed a reduced incidence of fetal acidosis (umbilical artery pH < 7.20) at cesarean delivery during spinal anesthesia when a combination of phenylephrine and ephedrine was used as first line vasopressor therapy, compared with using ephedrine alone.

Methods

The study was randomized and double blind. It compared phenylephrine 100 microg/ml (phenylephrine group), ephedrine 3 mg/ml (ephedrine group), and phenylephrine 50 microg/ml combined with ephedrine 1.5 mg/ml (combination group), given by infusion, to maintain maternal systolic arterial pressure at baseline during spinal anesthesia for elective cesarean delivery.

Results

Fetal acidosis was less frequent in the phenylephrine group (1 of 48) (P = 0.004) and less frequent in the combination group (1 of 47) (P = 0.005) than in the ephedrine group (10 of 48). The mean systolic arterial pressure was similar for the three groups: Phenylephrine group median 98% (IQR 94-103) of baseline, ephedrine group 100% (96-106) and combination group 101% (97-108) (P = 0.11). The mean heart rate was higher in the ephedrine group (median 107% [IQR 99-118] of baseline) than in the phenylephrine group (88% [82-98]) (P < 0.0001), or the combination group (96% [86-102]) (P < 0.0001). Nausea and vomiting were less frequent in the phenylephrine group (nausea 17%, vomiting 0%) than in the ephedrine group (nausea 66%, vomiting 36%) (P < 0.0001), or the combination group (nausea 55%, vomiting 18%) (P < 0.0001).

Conclusions

Giving phenylephrine alone by infusion at cesarean delivery was associated with a lower incidence of fetal acidosis and maternal nausea and vomiting than giving ephedrine alone. There was no advantage to combining phenylephrine and ephedrine because it increased nausea and vomiting, and it did not further improve fetal blood gas values, compared with giving phenylephrine alone.
Functional μ Opioid Receptors Are Reduced in the Spinal Cord Dorsal Horn of Diabetic Rats
Authors: Chen Shao-Rui , Sweigart Kristi L. , Lakoski Joan M. , Pan Hui-Lin
Published: August 2004

Background

The mechanisms of decreased spinal analgesic potency of morphine in neuropathic pain are not fully known. Agonist-stimulated [35S]GTPgammaS receptor autoradiography has been used to measure receptor activation of G proteins in vitro. Using this technique, we determined changes in the functional mu opioid receptors in the spinal dorsal horn in diabetic rats.

Methods

Rats were rendered diabetic with an intraperitoneal injection of streptozotocin. The lumbar spinal cord was obtained from age-matched normal and diabetic rats 4 weeks after streptozotocin treatment. [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO, 10 microm)-stimulated [35S]GTPgammaS binding was performed in both tissue sections and isolated membranes.

Results

The DAMGO-stimulated [35S]GTPgammaS binding in the spinal dorsal horn was significantly reduced (approximately 37%) in diabetic rats compared with normal rats. However, [35S]GTPgammaS bindings in the spinal dorsal horn stimulated by other G protein-coupled receptor agonists, including [D-Pen2,D-Pen5]-enkephalin, R(-)N6-(2-phenylisopropyl)-adenosine, and WIN-55212, were not significantly altered in diabetic rats. The basal [35S]GTPgammaS binding in the spinal dorsal horn was slightly (approximately 13%) but significantly increased in diabetic rats. Western blot analysis revealed no significant difference in the expression of the alpha subunits of G(i) and G(o) proteins in the dorsal spinal cord between normal and diabetic rats.

Conclusions

These data suggest that the functional mu opioid receptors in the spinal cord dorsal horn of diabetic rats are reduced. The impaired functional mu opioid receptors in the spinal cord may constitute one of the mechanisms underlying the reduced spinal analgesic effect of mu opioids in diabetic neuropathic pain.
Alcohol, Estrogen Replacement Therapy, and Visuospatial Processes in Postmenopausal Women
Authors: Tivis Laura J. , Green Michelle D. , Nixon Sara Jo , Tivis Rick D.
Published: August 2004

Background: Studies suggest that moderate drinking may benefit cognition and the effect may favor women. This study investigated effects of moderate drinking on visuospatial functioning in postmenopausal women. Visuospatial processes are sensitive to alcohol abuse and are thought to be sensitive to hormonal fluctuations. Three questions were posed in order to: explore visuospatial processes in moderate‐drinking and abstaining postmenopausal women, assess visuospatial differences in women using no estrogen replacement therapy (No‐ERT), ERT alone (ERT‐only), and ERT with progestin (ERT+Pro), and identify alcohol/ERT interactions associated with visuospatial performance.

Methods: Two hundred fourteen postmenopausal women participated (75 No‐ERT; 63 ERT‐only; 76 ERT+Pro. All were moderate drinkers or teetotalers and all received the Block Design test from the Wechsler Adult Intelligence Scale–Revised. A raw score was calculated and progress at 30‐sec intervals was assessed.

Results: ANOVA revealed an alcohol main effect [F (3,202) = 4.74; p < 0.004] on 60‐ to 120‐sec change scores. Teetotalers had significantly smaller change scores (less improvement) compared with all levels of drinkers. ANOVA on design 9 (the most difficult trial) revealed an ERT main effect [F (3,202) = 4.37; p < 0.02]. ERT nonusers scored significantly lower than ERT‐only and ERT+Pro groups. A design 9 trend toward an alcohol × ERT interaction was noted [F (6,202) = 1.93; p < 0.08], and a design 9 time × alcohol interaction was revealed [F (6,404) = 2.65; p < 0.02].

Conclusions: These data suggest that moderate drinking may be positively associated with visuospatial processes in postmenopausal women. They also suggest that ERT, alone and with progestin, is positively associated with visuospatial processes, but only when the task is difficult. These findings support Kaplan's assertion that subtle performance deficits may not be detectible with traditional endpoint measures. A provocative alcohol × ERT trend suggests that alcohol consumption should be considered in studies of ERT effects on cognitive ability.
A 6‐Month Controlled Naltrexone Study: Combined Effect With Cognitive Behavioral Therapy in Outpatient Treatment of Alcohol Dependence
Authors: Balldin J. , Berglund M. , Borg S. , Månsson Marianne , Bendtsen P. , Franck J. , Gustafsson L. , Halldin J. , Nilsson L.‐ H. , Stolt G. , Willander A.
Published: August 2004

Background: In several studies, patients with alcohol dependence treated with the opioid antagonist naltrexone have shown fewer relapses to heavy drinking than those receiving placebo. An interaction between the naltrexone effect and the type of psychological therapy has been observed.

Methods: A 6‐month, double‐blind, placebo‐controlled, parallel‐group study was performed at 10 different investigation sites. After a placebo run‐in period of 1 week, 118 patients were randomized into 4 treatment groups—50 mg of naltrexone daily or placebo in combination with either cognitive behavioral therapy (CBT) or supportive therapy. The CBT was performed over nine sessions according to the manual of Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity). The supportive therapy was defined as “the treatment as usual.” Alcohol consumption, craving, carbohydrate‐deficient transferrin, medication compliance by tablet count, and adverse clinical events were assessed at all visits. Other liver enzymes and psychiatric symptoms were also determined.

Results: Ninety‐one (77%) patients completed the study, and 92 (78%) were 80% compliant with the medication regimen. A lower percentage of heavy‐drinking days was shown in the naltrexone group (p= 0.045) compared with the placebo group, as was a lower craving score (p= 0.029). These results are supported by the lower levels of liver enzyme activities (p < 0.010 for aspartate aminotransferase, alanine aminotransferase, and γ‐glutamyltransferase), but not by the carbohydrate‐deficient transferrin levels, in the naltrexone group. The mean time period before the first day of heavy drinking was longer for the group treated with CBT (p= 0.010), especially in combination with naltrexone (p= 0.007). Naltrexone was well tolerated, and no patients discontinued the study due to side effects.

Conclusions: This study supports the effect of naltrexone in outpatient treatment of alcohol dependence and suggests that a beneficial interaction effect with CBT can be expected.
Auditory P3 in Female Alcoholics
Authors: Suresh Sudha , Porjesz Bernice , Chorlian David B. , Choi Keewhan , Jones Kevin A. , Wang Kongming , Stimus Arthur , Begleiter Henri
Published: August 2004

Background:The P3 (P300) has been considered to be a phenotypical marker of the risk for alcoholism. Although reductions in visual P3 in male and female alcoholics have been replicated, studies of auditory target P3 have been inconsistent. Our objective was to study the magnitude of auditory P3 reduction in female alcoholics and to establish the association between P3 reduction and alcoholism while taking into account comorbid depression and psychoactive drug dependence. The characteristics of P3 reduction were further examined by studying the reduction in family history–positive and –negative individuals.

Methods:Auditory target P3s recorded from 61 scalp electrodes in female alcoholics (n= 71) were compared with P3s from female controls (n= 159) ranging in age from 18 to 50 years. The amplitudes and latencies were statistically analyzed, by using repeated‐measures ANOVA, in six regional electrode arrays and at representative electrode sites, with age and comorbid depression as covariates. The effects of family density and clinical variables such as depression and drug dependence were also examined with correlation analysis.

Results:Alcoholic women had significantly lower P3 amplitudes in all six regions and at midline electrode sites. The reductions were not associated with comorbid depression, as shown by low correlations and similar P3 amplitudes at Pz in female alcoholics with and without depression. The P3 amplitudes in women with a high family density were smaller than those in women with a low family density of alcohol dependence. Drug dependency did not influence P3 amplitude, as shown by similar responses in drug‐dependent and non–drug‐dependent alcoholic women.

Conclusions:These findings highlight the significance of P3 reductions associated with alcoholism in women, independently of comorbid depression. Family density effects further support the evidence that these findings are heritable. These results suggest that P3 can be considered as a phenotypical marker of vulnerability to alcoholism in women.
The Search for Genes Related to a Low‐Level Response to Alcohol Determined by Alcohol Challenges
Authors: Wilhelmsen Kirk C. , Schuckit Marc , Smith Tom L. , Lee James V. , Segall Samantha K. , Feiler Heidi S. , Kalmijn Jelger
Published: August 2004

Background: A low level of response (LR) to alcohol seems to relate to a substantial proportion of the risk for alcoholism and to have significant heritability.

Methods: This report describes the results of a genome‐wide segregation analysis for the first 139 pairs of full siblings by using an alcohol challenge protocol as a direct measure of LR. Subjects from 18 to 29 years old were selected if the original screen indicated they had an alcohol‐dependent parent, reported a personal history of drinking but had no evidence of alcohol dependence, and had a full sibling with similar characteristics. Body sway and Subjective High Assessment Scale scores were measured at baseline and at regular intervals after the administration of a measured dose of alcohol. Participants and available parents were genotyped for 811 microsatellite markers, and resulting data were analyzed with a variance component method.

Results: Nine chromosome regions with logarithm of the odds ratio (LOD) between 2.2 and 3.2 were identified; several had previously been implicated regarding phenotypes relevant to alcoholism and the LR to alcohol. Several regions identified in the previous linkage study by using a retrospective self‐report questionnaire were potentially confirmed by this study. The strongest evidence was on chromosomes 10, 11, and 22.

Conclusions: Several chromosomal areas seem to relate to the low LR to alcohol as a risk factor for alcohol dependence.
Moderators of the Relationship Between Alcohol Dependence and Suicide and Medically Serious Suicide Attempts: Analyses of Canterbury Suicide Project Data
Authors: Conner Kenneth R. , Beautrais Annette L. , Conwell Yeates
Published: August 2004

Background: Preliminary data indicate that age, gender, and mood disorder moderate the association of alcohol dependence and suicide. The purpose of this study was to evaluate potential moderators of the relationship between alcohol dependence and suicide and medically serious suicide attempts by using case‐control data gathered in the Canterbury region of New Zealand for the Canterbury Suicide Project.

Methods: Data on 193 suicide decedents, 240 medically serious suicide attempters, and 984 community controls, all age 18 and over, were gathered by using psychological autopsy methodology. Multinomial logistic analyses were used to compare the two case groups to controls on demographic and diagnostic variables. Moderating effects were evaluated based on significant statistical interactions of predictors with alcohol dependence.

Results: The association of alcohol dependence and suicide (but not medically serious attempts) was amplified with increased age. Neither mood disorder nor gender moderated the relationship between alcohol dependence and suicide. Increased age amplified the association of mood disorder and suicide, whereas decreased age strengthened the association of mood disorder and medically serious suicide attempts.

Conclusions: Older age may serve as a marker for a construct (e.g., aggression/impulsivity) that underlies the failure to mature out of alcoholism, or a late‐onset subtype of alcoholism prone to negative affect, accounting for the association of older age and suicide in this population. Older age also may merely reflect longer duration of the deleterious effects of alcoholism.
Deletion of the Fyn‐Kinase Gene Alters Behavioral Sensitivity to Ethanol
Authors: Boehm Stephen L. , Peden Laura , Chang Rose , Harris R. Adron , Blednov Yuri A.
Published: August 2004

Background: An earlier study showed that deletion of the fyn‐kinase gene enhanced sensitivity to ethanol's sedative hypnotic effects and suggested that this was associated with diminished fyn‐kinase phosphorylation of NMDA receptors. The authors of that study speculated that this resulted in an inability of the null mutants to develop acute tolerance to ethanol, leading to the longer ethanol‐induced sleep times. However, in vivo acute tolerance to ethanol was not examined directly.

Methods: To address the role of fyn‐kinase in mediating acute tolerance, as well as sensitivity to several other behavioral effects of ethanol, we studied an independently generated population of fyn null mutant and wild‐type mice.

Results: Homozygous mutants exhibited longer ethanol sleep times that could not be attributed to differences in initial sensitivity, and impaired acute tolerance to the motor incoordinating effects of ethanol as measured by using the stationary dowel, but not the rotarod. Fyn‐kinase null mutants were more sensitive to the anxiolytic effects of ethanol when tested using the elevated plus maze, and males displayed a lower preference for ethanol in a two‐bottle choice paradigm. Finally, mutant and wild‐type mice did not differ in sensitivity to the hypothermic effects of ethanol. The genotypes also did not differ in blood‐ethanol clearance, eliminating a metabolic explanation for these behavioral differences.

Conclusions: These results show that fyn‐kinase modulates acute tolerance to ethanol and suggest a role for fyn in mediating ethanol's anxiolytic and reinforcing properties.
Ethanol Increases Extracellular Dopamine Concentration in the Ventral Striatum in C57BL/6 Mice
Authors: Tang Amanda , George Magnia A. , Randall Judith A. , Gonzales Rueben A.
Published: August 2004

Background: Mesolimbic dopamine is thought to play a role in the reinforcing properties of ethanol, but ethanol‐induced changes in extracellular dopamine in the ventral striatum have not been well characterized in mouse models.

Methods: Two experiments were used to characterize the pharmacodynamic response of ethanol in the ventral striatum in C57BL/6 mice. The first experiment determined the effect of ethanol on ventral striatal dopamine in male and female mice after intraperitoneal injection of either 2.0 g/kg ethanol or saline. The second experiment was a replication in males, except that the mice were habituated to intraperitoneal injections before the dialysis experiment.

Results: Distinct patterns of dopamine activity in response to ethanol were demonstrated in male and female C57BL/6 mice. A significant increase in dialysate dopamine relative to saline injection was observed in females but not in males. With habituation to intraperitoneal injection before the dialysis experiment, ethanol administration caused a significant dopamine response in males as well. A linear decline was observed in dialysate ethanol concentrations after the peak concentration was reached. Concurrent analysis of the time course of dopamine and ethanol content showed that the dopamine response declined significantly faster than the ethanol concentrations.

Conclusions: The C57BL/6 mouse strain is a justifiable model system for studying the mechanisms involved in ethanol regulation of mesolimbic dopamine activity. Habituation to intraperitoneal injection should be used in male C57BL/6 mice for experiments in which the dopamine response is measured after intraperitoneal injection of a drug. The dissociation between dopamine and ethanol may indicate an acute neural adaptation to ethanol‐induced dopamine response in the ventral striatum after a single ethanol injection.
Hepatic Apoptosis and Proliferation in Male and Female Rats Fed Alcohol: Role of Cytokines
Authors: Colantoni Alessandra , Idilman Ramazan , De Maria Nicola , La Paglia Nancy , Belmonte Joseph , Wezeman Frederick , Emanuele Nicholas , Van Thiel David H. , Kovacs Elizabeth J. , Emanuele Mary Ann
Published: August 2004

Background: The female liver is more sensitive to the toxic effect of chronic alcohol intake than the male liver. The aim of the study was to compare the influence of gender and sex hormonal status on apoptosis and cell proliferation following chronic ethanol intake.

Methods: Male and female rats were pair fed for 8 weeks a liquid diet containing 36% of their total daily calories as ethanol (ETOH group) or sucrose (control group). Liver samples were analyzed for apoptosis and hepatocyte proliferation by immunohistochemistry. The hepatic production of factors able to influence cell death and proliferation, such as tumor necrosis factor alpha (TNFα) and interleukin 6 (IL‐6) were determined.

Results: In both male and female rats, ethanol intake promoted apoptosis in the liver. This effect of ethanol was more evident in female than male rat livers. Hepatic TNFα levels, which promote apoptosis, are significantly more elevated in female than in male livers. Hepatic IL‐6 production, which promotes hepatocyte proliferation, was induced by ethanol only in males, but not female animals.

Conclusion: This observed difference in cytokine responses may contribute to the enhanced sensitivity of female liver to EtOH‐induced injury.
Testing Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (The COMBINE Study): A Pilot Feasibility Study
Authors:   The COMBINE Study Research Group
Published: August 2004

Background: Medications (such as naltrexone and acamprosate) as well as behavioral therapies have been previously reported to be effective in the reduction of alcohol intake and to prevent relapse drinking. However, the efficacy of using several medications alone or together in combination with behavioral therapies has not been widely investigated. The purpose of this study was to evaluate the feasibility of this combined therapy approach to apply it to a larger scale multisite clinical trial. Outcome focused on recruitment, retention, adherence to study parameters and medication, physical complaints, and physiologic toxicity.

Methods: At 11 sites, 108 individuals with alcohol dependence were randomized in a double blind fashion to receive placebo, naltrexone, or acamprosate alone or in combination. In addition, some individuals were randomized to receive Medical Management (MM) provided by a health care practitioner alone or in combination with an enhanced behavioral intervention, Combined Behavioral Intervention (CBI), delivered by a trained therapist. A final group received CBI alone without pills. All participants were treated and assessed for a maximum of 16 weeks.

Results: The attendance at therapy and research visits, and medication adherence and tolerability were good with no statistical differences between the medication or behavioral intervention groups. Over 75% of participants completed the week‐16, end of study, assessment and the average medication adherence (percent of total pills taken) was about 65%. The level and types of physical complaints were not unexpected and similar among the medication and placebo groups. There were no group differences in liver or kidney toxicity. Importantly, the combination of naltrexone and acamprosate did not present significantly more physical complaints than either alone.

Conclusions: Sufficient numbers of alcohol dependent participants can be recruited and retained in a relatively sophisticated outpatient trial combining medications and behavioral interventions. Participant adherence to the trial protocol including medication regimens was at acceptable levels. Physical complaints and organ toxicity were within expected and acceptable levels. Based on these results a larger scale study utilizing these methodologies appears feasible.
The evolution of ICT‐based learning environments: which perspectives for the school of the future?
Authors: Bottino Rosa Maria
Published: August 2004

This paper briefly outlines the evolution of ICT‐based learning environments discussing some of the main aspects that have characterised such evolution (eg, technological evolution, changed cognitive and pedagogical frameworks, changed role assigned to ICT‐based systems in education). The objective is to point out how the implementation of innovative learning environments, based on advanced technology, is the result of the strict interrelation between educational and cognitive theories, technological opportunities and teaching and learning needs. In this paper some indications for current and future evolution are evidenced. Reference is made to an ICT‐based multi‐environment system that supports teaching and learning activities in the domain of arithmetic problem solving at compulsory school level.