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Sample records for baclofen

  1. Baclofen Oral

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    Baclofen acts on the spinal cord nerves and decreases the number and severity of muscle spasms caused by multiple ... or do not go away: drowsiness dizziness weakness confusion upset stomach If you experience either of the ...

  2. An unusual case of baclofen abuse

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    Soumitra Das

    2016-01-01

    Full Text Available Baclofen was initially used for the treatment of spastic conditions. Last decade has seen its emergence as a treatment of profound interest in alcohol dependence, opiates and cocaine abuse, and tobacco addiction. However, the published literature on baclofen abuse is sparse. Here, we report a patient with baclofen abuse.

  3. Intrathecal baclofen therapy for spastic hypertonia.

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    Ivanhoe, C B; Tilton, A H; Francisco, G E

    2001-11-01

    Intrathecal baclofen is perhaps the most effective treatment for significant spasticity regardless of the origin. For appropriately selected patients, it can provide qualitative and quantitative improvements in quality of life. This article discusses the practical aspects and patient selection, trial, implant, and ongoing management of patients with intrathecal baclofen pump therapy.

  4. Baclofen overdose treated with continuous venovenous hemofiltration

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    Meulendijks, Didier; Khan, Saheed; Koks, Cornelis H W; Huitema, Alwin D R; Schellens, Jan H M; Beijnen, Jos H.

    2015-01-01

    Purpose: Overdose with baclofen, a derivative of the inhibitory neurotransmitter γ-aminobutyric acid, may lead to severe respiratory and central nervous system depression and can be life-threatening. Prolonged half-lives of baclofen, of up to 34 h, have been reported in patients after overdose. Hemo

  5. Influence of adrenergic and cholinergic mechanisms in baclofen induced analgesia.

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    Tamayo, L; Rifo, J; Contreras, E

    1988-01-01

    1. Baclofen induced analgesia was confirmed by means of the mouse hot plate test. 2. Physostigmine significantly increased the response to baclofen whilst neostigmine was ineffective. Baclofen analgesia was reduced by atropine. 3. The response to baclofen was increased by the administration of tolazoline, propranolol and nadolol. In contrast, the analgesic response to morphine was attenuated by the antiadrenergic drugs phenoxybenzamine, tolazoline and nadolol.

  6. Treatment of recalcitrant cough with baclofen

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    Paolo Agostinis

    2013-04-01

    Full Text Available Background: Chronic dry cough is a debilitating symptom often refractory to standard antitussive therapy. It may result from increased sensitivity of the cough reflex. Baclofen, an agonist of gamma-aminobutyric acid (GABA, has been shown, in animals, to have antitussive activity via a central mechanism. In normal subjects baclofen has been revealed ability to inhibit capsaicininduced cough and cough due to angiotensin-converting enzyme (ACE inhibitors. In addition, chronic therapy with baclofen has been shown to reduce cough reflex sensitivity in subjects with cervical spinal cord injury. Clinical cases: We describe two patients with chronic refractory cough who obtained symptomatic improvement after oral baclofen administration. The antitussive effect of baclofen, usually used for treatment of spasticity associated with multiple sclerosis and spinal cord lesions, can be explained by central inhibition, but may also involve peripheral inhibitory mechanisms.

  7. Muscle relaxant and neurotoxic activities of intrathecal baclofen in rats.

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    Kuroiwa, Miho; Kitano, Yutaka; Takasuna, Kiyoshi; Manabe, Sunao; Saito, Takao

    2009-11-01

    Intrathecal baclofen therapy by the continuous intrathecal infusion of baclofen has been shown to be an effective treatment for spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis and other disorders. To demonstrate the efficacy and safety of intrathecal baclofen therapy, we investigated the muscle relaxant and neurotoxic activities of intrathecal baclofen in rats, compared with intravenous baclofen. Intrathecal and intravenous administration of baclofen dose-dependently inhibited the anemic decerebrate rigidity with ED(50) values of 0.31microg/animal (=1.1-1.3microg/kg) and 0.43mg/kg, respectively. Intrathecal administration of baclofen induced no noticeable changes in a spontaneous electroencephalogram at 30microg/animal. Intravenous administration of baclofen induced an abnormal electroencephalogram with flat waves in all the animals and the no-observed-effect level was estimated to be 5mg/kg. In some animals, intravenous administration of baclofen induced sporadic spikes or sharp waves with background flat waves, indicating inhibitory and excitatory effects on the central nervous system. In conclusion, intrathecal administration of baclofen dose-dependently inhibited anemic decerebrate rigidity in rats and the effective dose was more than 300 times lower than that of intravenous baclofen. The safety margin of intrathecal baclofen was greater than that of intravenous baclofen (> or =97 versus 12). These results suggest that intrathecal baclofen therapy is superior to systemic baclofen therapy in both efficacy and safety.

  8. Correlates of baclofen effectiveness in alcohol dependence

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    Lekhansh Shukla

    2015-01-01

    Full Text Available Alcohol dependence is a global concern. Baclofen has shown promise as an anti-craving agent but its efficiency remains to be settled. We reviewed 549 male cases diagnosed with alcohol dependence who received Acamprosate (201 or Baclofen (348. ′Time to first drink′ was compared between two groups and multiple regression analysis was done in baclofen group to identify correlates of effectiveness. There was a significant difference in outcome measure between Baclofen (M = 4.44, SD = 3.75 and Acamprosate group (M = 3.73, SD = 2.19; t (547 = 2.45, P = 0.01. Initial regression analysis with six predictor variables (average daily alcohol units, current age, age at onset of dependence, family history, duration of dependence and dose of baclofen in mg/day showed significant correlation of outcome variable with only two predictor variables - dose of baclofen and average daily intake. Using the hierarchical method it was found that ′dose of baclofen′ and ′average alcohol intake′ explain a significant amount of variance in ′time to first drink′. [F (1, 345 = 182.8, P < 0.001, R2 = 0.52, R2 adjusted = 0.51]. This information can be used to select patients in long term longitudinal studies and may explain variable results seen in clinical trials of baclofen done earlier.

  9. Baclofen as an analgesic in chronic peripheral nerve disease.

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    Terrence, C F; Fromm, G H; Tenicela, R

    1985-01-01

    Baclofen has shown analgesic properties in a number of animal studies but has failed as a conventional analgesic in the human postoperative dental pain model. In order to test baclofen's analgesic properties in more chronic pain conditions, we selected postherpetic neuralgia and diabetic neuropathy pain as possible trial diseases for baclofen analgesia. 15 patients with postherpetic neuralgia and 10 with diabetic neuropathy pain were treated with baclofen. In the spinal postherpetic neuralgia group and diabetic neuropathy group, there was little evidence of analgesic effect. 6 of 7 patients with facial postherpetic neuralgia had a good response to baclofen during the 3-week trial. Baclofen does not appear to be a conventional analgesic.

  10. R(+-baclofen, but not S(--baclofen, alters alcohol self-administration in alcohol-preferring rats

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    Irene eLorrai

    2016-04-01

    Full Text Available Racemic baclofen [(±-baclofen] has repeatedly been reported to suppress several alcohol-motivated behaviors, including alcohol drinking and alcohol self-administration, in rats and mice. Recent data suggested that baclofen may have bidirectional, stereospecific effects, with the more active enantiomer, R(+-baclofen, suppressing alcohol intake and the less active enantiomer, S(--baclofen, stimulating alcohol intake in mice. The present study was designed to investigate whether this enantioselectivity of baclofen effects may extend also to the reinforcing properties of alcohol in rats. To this end, selectively bred Sardinian alcohol-preferring (sP rats were initially trained to lever-respond on a Fixed Ratio (FR 4 (FR4 schedule of reinforcement for alcohol (15%, v/v in daily 30-min sessions. Once responding had stabilized, rats were tested with vehicle, (±-baclofen (3 mg/kg, R(+-baclofen (0.75, 1.5, and 3 mg/kg, and S(--baclofen (6, 12, and 24 mg/kg under the FR4 schedule of reinforcement. Treatment with 3 mg/kg (±-baclofen reduced the number of lever-responses for alcohol and estimated amount of self-administered alcohol by approximately 60% in comparison to vehicle treatment. R(+-baclofen was approximately twice as active as (±-baclofen: treatment with 1.5 mg/kg R(+-baclofen decreased both variables to an extent similar to that of the decreasing effect of 3 mg/kg (±-baclofen. Conversely, treatment with all doses of S(--baclofen failed to affect alcohol self-administration. These results (a confirm that non-sedative doses of (±-baclofen effectively suppressed the reinforcing properties of alcohol in sP rats and (b apparently do not extend to operant alcohol self-administration in sP rats the capability of S(--baclofen to stimulate alcohol drinking in mice.

  11. Role of hemodialysis in baclofen overdose with normal renal function

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    Lorraine S Dias

    2011-01-01

    Full Text Available The treatment of baclofen overdose is primarily supportive. There have been case reports of hemodialysis being used in patients with chronic kidney disease with baclofen overdose. A case report of hemodialysis in a baclofen-overdose patient with normal renal function is presented. Review of literature has also been provided.

  12. Intrathecal baclofen withdrawal: A rare cause of reversible cardiomyopathy.

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    Awuor, Stephen O; Kitei, Paul M; Nawaz, Yassir; Ahnert, Amy M

    2016-03-01

    Baclofen is commonly used to treat spasticity of central etiology. Unfortunately, a potentially lethal withdrawal syndrome can complicate its use. This is especially true when the drug is administered intrathecally. There are very few cases of baclofen withdrawal leading to reversible cardiomyopathy described in the literature. The authors present a patient with a history of chronic intrathecal baclofen use who, in the setting of acute baclofen withdrawal, develops laboratory, electrocardiogram, and echocardiogram abnormalities consistent with cardiomyopathy. Upon reinstitution of intrathecal baclofen, the cardiomyopathy and associated abnormalities quickly resolve. Although rare, it is crucial to be aware of this reversible cardiomyopathy to ensure its prompt diagnosis and treatment.

  13. Iatrogenic Baclofen Neurotoxicity in ESRD: Recognition and Management.

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    Roberts, John K; Westphal, Scott; Sparks, Matthew A

    2015-01-01

    Baclofen is an oral derivative of gamma-aminobutyric acid (GABA) used to treat muscular spasticity from disorders of the central nervous system. However, it is also being used for a variety of other conditions such as musculoskeletal pain, myoclonus, and alcohol withdrawal. The elimination of baclofen is heavily dependent on intact renal function, and the contraindication for use in patients with insufficient renal function is not well recognized by healthcare providers. Here, the authors report a series of mild to severe cases of baclofen intoxication in patients with end-stage renal disease. In all cases, baclofen was initiated by either inpatient or outpatient healthcare providers and the patients generally presented with altered mentation, somnolence, and/or respiratory depression. All patients were treated with aggressive hemodialysis and made a full recovery. This paper will briefly review the literature regarding baclofen intoxication, safety of baclofen use in renal disease, and efficacy of extracorporeal therapy in the treatment of baclofen intoxication.

  14. Intrathecal Baclofen Therapy: Benefits and Complications

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    Zdolsek, Helena Aniansson; Olesch, Christine; Antolovich, Giuliana; Reddihough, Dinah

    2011-01-01

    Background: Spasticity and dystonia in children with cerebral palsy has been treated with intrathecal baclofen therapy (ITB) at the Royal Children's Hospital, Melbourne, Australia (RCH) since 1999. Methods: The records of children having received or still receiving ITB during the period September 1999 until August 2005 were studied to evaluate…

  15. Baclofen for alcohol dependence: Relationships between baclofen and alcohol dosing and the occurrence of major sedation.

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    Rolland, Benjamin; Labreuche, Julien; Duhamel, Alain; Deheul, Sylvie; Gautier, Sophie; Auffret, Marine; Pignon, Baptiste; Valin, Thomas; Bordet, Régis; Cottencin, Olivier

    2015-10-01

    High-dose baclofen, i.e., 300 mg/d or more, has recently emerged as a strategy for treating alcohol dependence. The impact that the co-exposure of large amounts of alcohol and baclofen has on sedation is unclear. In a prospective cohort of 253 subjects with alcohol dependence, we collected daily alcohol and baclofen doses across the first year of baclofen treatment and the monthly maximum subjective sedation experienced by each patient (0-10 visual analog scale). For each patient-month, we determined the average weekly alcohol consumption (AWAC; standard-drinks/week) and the maximum daily dose of baclofen (DDB; mg/d). The occurrence of an episode of major sedation (EMS) during a patient-month was defined as a sedation score ≥7. The relationship between the EMS occurrence and the concurrent AWAC and DDB was investigated using a generalized estimating equation model. In total, 1528 patient-months were compiled (70 with an EMS). Univariate analyses demonstrated that the rate of patient-month to EMS increased gradually with AWAC (p35. There was also a significant gradual risk for EMS associated with DDB (35 of 1.22 (95%CI, 1.08-1.38) versus 1.11 (95%CI, 0.96-1.29) in AWAC=1-35, and 0.95 (95%CI, 0.76-1.19) in AWAC=0. The level of sedation observed in patients using baclofen for alcohol dependence appears to directly depend on the immediate doses of both the baclofen and the alcohol.

  16. Unintentional baclofen intoxication in the management of alcohol use disorder.

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    Reichmuth, Philipp; Blanc, Anne-Laure; Tagan, Damien

    2015-09-22

    In recent years, there has been a growing interest in using baclofen for the management of alcohol use disorder. This off-label indication usually involves high doses of the medication. We report a case of severe baclofen overdose in a 66-year-old man. The patient was found severely agitated, and he presented with delirium and auditory hallucinations. At hospital admission, his daily dose was 180 mg baclofen. He was admitted to the intensive care unit for sedation and supportive care. When sedation was withdrawn, the patient presented with a normal neurological status. In this clinical context, baclofen intoxication was suspected. This was confirmed by measuring blood baclofen levels. This intoxication was probably mediated by a combination of risk factors including a high daily dose of baclofen and acute renal failure, conducive to drug accumulation.

  17. Pronounced hypothermic synergy between systemic baclofen and NOS inhibitor.

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    Rawls, Scott M; Baron, David A; Gomez, Teresa; Jacobs, Kyle; Tallarida, Ronald J

    2004-10-19

    Baclofen was administered to rats systemically (intraperitoneal, i.p.) by itself or with L-NAME. Baclofen (1-7.5 mg/kg, i.p.) evoked dose-dependent hypothermia. L-NAME (50 mg/kg, i.p.) was ineffective. For combined administration, L-NAME increased the relative potency of baclofen (F=10.77, p<0.05), indicating multiplicative interaction and synergism. The present data reveal a surprising and significant interaction between nitric oxide synthase (NOS) and baclofen-induced hypothermia.

  18. Baclofen for narcolepsy with cataplexy: two cases

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    Lee EK

    2015-07-01

    Full Text Available Elliott Kyung Lee,1,2 Alan Bruce Douglass1,2 1Department of Psychiatry, Faculty of Medicine, Institute of Mental Health Research, University of Ottawa, 2Royal Ottawa Mental Health Center, Ottawa, ON, Canada Abstract: Narcolepsy is a disabling sleep disorder characterized by daytime hypersomnolence. Those with cataplexy have spells of muscle weakness precipitated by strong emotions, especially laughter or surprise. Cataplexy treatments include antidepressants or a GABA-B agonist, gamma hydroxybutyrate (GHB. GHB is the most effective treatment for cataplexy, but is expensive and can have significant side effects. A recent report of a murine model of narcolepsy-cataplexy suggests R-baclofen has potential efficacy against cataplexy. We report on two narcolepsy patients with multiple daily cataplexy episodes, one of whom had been effectively treated with GHB, but had to discontinue it for unrelated medical reasons. Both subsequently tried baclofen and experienced almost complete resolution of cataplexy. This report suggests baclofen can be an effective treatment for cataplexy in humans and warrants further study. Keywords: hypersomnolence, gamma hydroxybutyrate, excessive daytime sleepiness

  19. A nationwide register-based survey of baclofen toxicity.

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    Kiel, Louise Bendix; Hoegberg, Lotte Christine Groth; Jansen, Tejs; Petersen, John Asger; Dalhoff, Kim Peder

    2015-05-01

    To study the use and misuse (poisonings) of baclofen in the time period of 2007-2012 and to evaluate the severity and clinical symptoms of poisonings including ingested baclofen. The National Patient Register (NPR) was searched for admissions due to baclofen poisonings from 2007 to 2012. The search was conducted with ICD-10 codes for poisoning, self-harm and suicide, and coupled with the baclofen ATC code. All enquiries about baclofen to the Danish Poison Information Centre (DPIC) in the same period were evaluated. Demographic and clinical data were extracted, and the poisonings were classified according to the Poison Severity Score. The number of baclofen poisonings did not increase from 2007 to 2012. Thirty-eight admissions with baclofen poisoning were registered at the NPR; however, only one-third of the reviewed DPIC cases were registered at the NPR with the correct coding. In the group of severely poisoned patients (PSS 3), three patients had only ingested baclofen (mean 2000 mg; SD 500 mg) and eight patients had ingested baclofen together with alcohol or psychotropic drugs (mean 900 mg; SD 641 mg). All patients presented with deep coma and respiratory depression. Additionally, seizures and cardiovascular events (mild hypo- or hypertension and bradycardia) occurred. There is a substantial degree of underreporting of baclofen poisonings in Denmark. Symptoms of baclofen poisoning progress very fast, and toxicity was observed even with doses as low as 150 mg. We therefore recommend that observation and treatment of these patients should be carried out in an intermediate- or intensive care unit. The most important treatment is the maintenance of a protected airway and respiration.

  20. A Nationwide Register-Based Survey of Baclofen Toxicity

    DEFF Research Database (Denmark)

    Kiel, Louise Bendix; Hoegberg, Lotte Christine Groth; Jansen, Tejs

    2015-01-01

    To study the use and misuse (poisonings) of baclofen in the time period of 2007-2012 and to evaluate the severity and clinical symptoms of poisonings including ingested baclofen. The National Patient Register (NPR) was searched for admissions due to baclofen poisonings from 2007 to 2012. The sear...... and treatment of these patients should be carried out in an intermediate- or intensive care unit. The most important treatment is the maintenance of a protected airway and respiration.......To study the use and misuse (poisonings) of baclofen in the time period of 2007-2012 and to evaluate the severity and clinical symptoms of poisonings including ingested baclofen. The National Patient Register (NPR) was searched for admissions due to baclofen poisonings from 2007 to 2012. The search...... to the Poison Severity Score. The number of baclofen poisonings did not increase from 2007 to 2012. Thirty-eight admissions with baclofen poisoning were registered at the NPR; however, only one-third of the reviewed DPIC cases were registered at the NPR with the correct coding. In the group of severely poisoned...

  1. Increase of baclofen intoxications : risks involved and management

    NARCIS (Netherlands)

    Arbouw, M E L; Hoge, H L; Meulenbelt, J; Jansman, F G A

    2014-01-01

    Baclofen has been increasingly used in the treatment of alcohol withdrawal syndrome (AWS). We present a patient with AWS and psychiatric comorbidity who ingested 700 mg of baclofen. ICU admission was necessary for ventilatory support and symptomatic treatment. The patient was dismissed without seque

  2. Intestinal pseudo-obstruction following oral baclofen: An unusual complication

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    Vilvapathy Senguttuvan Karthikeyan

    2015-01-01

    Full Text Available Baclofen is a gamma- aminobutyric acid B (GABA B agonist used for the management of spasticity associated with spinal cord injury. Oral baclofen might cause constipation, but intestinal pseudo-obstruction is very rare. We report a 50-year-old male with spasticity following cervical discectomy (C3-4 on oral baclofen for 6 months with intestinal pseudo-obstruction. He had undergone open suprapubic cystostomy for traumatic urethral injury, 45 days prior to the presentation and adhesive intestinal obstruction was also considered a possibility. However, there were no air fluid levels on abdominal radiographs and ultrasound abdomen was non-contributory. Withdrawal of baclofen was therapeutic in this patient. This case is being reported to highlight the rare possibility of oral baclofen induced intestinal pseudo-obstruction.

  3. The incidence and management of tolerance in intrathecal baclofen therapy

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    Heetla, H. W.; Staal, M. J.; Kliphuis, C.; van Laar, T.

    2009-01-01

    Study design: Retrospective study. Objectives: To study the incidence and management of tolerance in patients treated with intrathecal baclofen (ITB) therapy. Setting: Department of neurology and neurosurgery, University Medical Center Groningen, The Netherlands. Methods: Medical records of all pati

  4. Differential effects of (-)-baclofen on Ia and descending monosynaptic EPSPs.

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    Jiménez, I; Rudomin, P; Enriquez, M

    1991-01-01

    1. In cats anesthetized with alpha-chloralose, population synaptic responses of motoneurons produced by stimulation of group I afferents were recorded from ventral roots with a sucrose gap or extracellularly from the motor pool. These responses were depressed, and often abolished, following the intravenous injection of 1-3 mg/kg of (-)-baclofen, a presumed GABAb agonist. 2. The monosynaptic population responses of motoneurons produced by stimulation of the ipsilateral ventromedial funiculus (VMF), the bulbar reticular formation or the vestibular nucleus, were also depressed following the administration of (-)-baclofen, but to a lesser degree than responses produced by stimulation of group I fibers. 3. Depression of the synaptic actions of Ia and of descending fibers following the administration of (-)-baclofen occurred without significant changes in the presynaptic volley recorded from the cord dorsum. However, in 3/4 experiments the intraspinally recorded Ia terminal potential was reduced following the injection of (-)-baclofen. The VMF terminal potentials were also depressed, but to a lesser degree. 4. Intracellular recordings from spinal motoneurons indicate that the (-)-baclofen-induced depression of the monosynaptic Ia- and VMF-EPSPs occurred without important changes in the time course of EPSP decay. This suggests that with the amounts used, postsynaptic changes were not contributing significantly to the EPSP depression. 5. It is suggested that (-)-baclofen depresses synaptic transmission probably by activation of GABAb receptors located at the intraspinal terminations of Ia and descending fibers. The lower sensitivity of VMF actions to (-)-baclofen would be accounted for by a relatively low density of baclofen receptors in descending fiber terminals.

  5. Retraction of an intrathecal baclofen infusion catheter following suprapubic cystotomy: a case report.

    NARCIS (Netherlands)

    Martens, F.M.J.; Somford, D.M.; Kuppevelt, D.H. van; Burg, M.J. van den; Heesakkers, J.P.F.A.

    2009-01-01

    INTRODUCTION: Intrathecal baclofen, administered via a Baclofen pump, is used for patients with spasticity. We report here a case of intrathecal catheter retraction following surgery. CASE REPORT: A male patient with adrenoleukodystrophy and a baclofen pump implant was admitted to the urology depart

  6. Clinical experience of baclofen in alcohol dependence: A chart review

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    Abhijit R Rozatkar

    2016-01-01

    Full Text Available Introduction: Craving is recognized as a formidable barrier in the management of patients with alcohol dependence. Among pharmacological agents that have been used in experimental studies for reduction in craving, baclofen appears to have a significant advantage over other agents. Methodology: The study is retrospective chart review of patients (n = 113 who have been treated with baclofen for alcohol dependence in a tertiary hospital of North India. Baseline assessments included sociodemography, motivation, quantity-frequency of alcohol use, and other alcohol-related clinical parameters. Weekly assessments, for a period of 4 weeks, were extracted from records which included dose of baclofen, craving intensity, and alcohol consumption. Results: The study sample was predominantly male, mean age of 41.49 (±9.75 years, most having a family history of substance use (70.97%, and many reporting binge use pattern in last year (49.46%. Baseline assessment revealed 48.7% of the sample was in precontemplation phase for alcohol use and 70% reported severe and persistent craving. This persistent craving was reported by only 15% of the sample by the end of 4 weeks treatment with baclofen (20–40 mg/day. Thirty-four percent of patients reported continued problematic use of alcohol by the end of 4 weeks. Conclusion: Our clinical experience suggests that baclofen reduces craving and alcohol consumption including in those with poor motivation. The drug causes few side effects and does not add to the intoxication effect of alcohol. Considering that baclofen is safe in those with liver cirrhosis and reduces withdrawal symptoms due to alcohol, a controlled trial comparing it with standard treatment is required.

  7. Review of Intrathecal Baclofen Therapy for Spastic and Rigidity Disorders

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    Obringer, S. John; Coffey, Kenneth M.

    2002-01-01

    Intrathecal baclofen therapy, a treatment for cerebral palsy and other spastic and rigidity disorders, is showing promise as an effective intervention. This article synthesizes both the medical and rehabilitation conceptual literature to update educators and related service providers as to the efficacy of this intervention. Implications for…

  8. Baclofen and gamma-hydroxybutyrate (GHB), a dangerous combination

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    Kamal, R.M.; Qurishi, R.; Jong, C.A.J. de

    2015-01-01

    Baclofen is a gamma-aminobutyric acid (GABA)-beta receptor agonist with a muscle relaxant effect. It increases GABA activity and reduces the production of glutamate and dopamine. The GABA precursor gamma-hydroxybutyrate (GHB) has gained popularity as a drug of abuse. For the first time, we report a

  9. Baclofen and y-hydroxybutyrate (GHB), a dangerous combination

    NARCIS (Netherlands)

    Kamal, R.M.; Qurishi, R.; Jong, C.A.J. de

    2015-01-01

    Baclofen is a γ-aminobutyric acid (GABA)-β receptor agonist with a muscle relaxant effect. It increases GABA activity and reduces the production of glutamate and dopamine. The GABA precursor γ-hydroxybutyrate (GHB) has gained popularity as a drug of abuse. For the first time, we report a case of a G

  10. The use of very high-doses of baclofen for the treatment of alcohol-dependence: a case series.

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    Renaud ede Beaurepaire

    2014-10-01

    Full Text Available Baclofen, particularly high-dose baclofen, has recently emerged as a treatment of major interest for alcohol-dependence. However, baclofen has many potentially dangerous side effects, and the maximal dose of baclofen that may be used is a matter of discussion. Here, the author analyses the medical charts of the last 100 patients seen in his clinic, 17 of whom have been taking a very high dose of baclofen, that is to say, more than 300mg per day. The analysis of the charts shows that the very high doses baclofen were justified in almost all the cases. Side effects are analyzed.

  11. How a Drug Shortage Contributed to a Medication Error Leading to Baclofen Toxicity in an Infant

    OpenAIRE

    Lau, Bonnie; Khazanie, Uma; Rowe, Emily; Fauman, Karen

    2016-01-01

    We report the case of a 4-month-old girl who developed encephalopathy, seizures, and respiratory compromise as a result of baclofen toxicity. After some investigation, the accidental ingestion of baclofen was caused by an error in compounding the patient's prescribed omeprazole with baclofen rather than sodium bicarbonate at a retail pharmacy. This error occurred because these two drugs, which were available as powders, were located side by side on the pharmacy shelf. The pharmacist further r...

  12. Resolution of the stereoisomers of baclofen by high performance liquid chromatography

    Energy Technology Data Exchange (ETDEWEB)

    Weatherby, R.P.; Allan, R.D.; Johnston, G.A.R. (Sydney Univ. (Australia))

    1984-01-01

    The GABA analogue baclofen (3-(p-chlorophenyl)-4-aminobutanoic acid) has stereospecific actions on the peripheral and central nervous systems. This paper describes the resolution of tritium-labelled baclofen by high performance liquid chromatography on a reverse-phase C18 column using a chiral mobile phase. The method, which may have general application to certain other GABA analogues, affords optically pure (+)- and (-)-baclofen labelled with tritium to high specific activity suitable for ligand binding and other neurochemical studies.

  13. Encephalopathy and Hypotonia due to Baclofen Toxicity in a Patient with End-Stage Renal Disease

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    Ijaz, Mohsin; Tariq, Hassan; KASHIF,MUHAMMAD; Marquez, Jose Gomez

    2015-01-01

    Patient: Female, 57 Final Diagnosis: Baclofen toxicity Symptoms: Encephalopathy • hypotonia Medication: Baclofen Clinical Procedure: Hemodialysis Specialty: Critical Care Objective: Unusual or unexpected effect of treatment Background: Baclofen is a centrally acting gamma-aminobutyric acid agonist used for the symptomatic relief of skeletal muscle spasm and spasticity in traumatic spinal cord lesions, multiple sclerosis, cerebral palsy, and stroke. It is also used in the treatment of chronic ...

  14. Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans

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    Raymundo Sanchez-Ponce

    2012-09-01

    Full Text Available STX209 is an exploratory drug comprising the single, active R-enantiomer of baclofen which is in later stage clinical trials for the treatment of fragile x syndrome (FXS and autism spectrum disorders (ASD. New clinical data in this article on the metabolism and pharmacokinetics of the R- and S-enantiomers of baclofen presents scientific evidence for stereoselective metabolism of only S-baclofen to an abundant oxidative deamination metabolite that is sterically resolved as the S-enantiomeric configuration. This metabolite undergoes some further metabolism by glucuronide conjugation. Consequences of this metabolic difference are a lower Cmax and lower early plasma exposure of S-baclofen compared to R-baclofen and marginally lower urinary excretion of S-baclofen after racemic baclofen administration. These differences introduce compound-related exposure variances in humans in which subjects dosed with racemic baclofen are exposed to a prominent metabolite of baclofen whilst subjects dosed with STX209 are not. For potential clinical use, our findings suggest that STX209 has the advantage of being a biologically defined and active enantiomer.

  15. Baclofen Withdrawal Presenting as Irritability in a Developmentally Delayed Child

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    C. Anthoney Lim

    2012-09-01

    Full Text Available Irritability in children has a broad differential diagnosis, ranging from benign processes to lifethreatening 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.

  16. Enantioresolution of (RS)-baclofen by liquid chromatography: A review.

    Science.gov (United States)

    Batra, Sonika; Bhushan, Ravi

    2017-01-01

    Baclofen is a commonly used racemic drug and has a simple chemical structure in terms of the presence of only one stereogenic center. Since the desirable pharmacological effect is in only one enantiomer, several possibilities exist for the other enantiomer for evaluation of the disposition of the racemic mixture of the drug. This calls for the development of enantioselective analytical methodology. This review summarizes and evaluates different methods of enantioseparation of (RS)-baclofen using both direct and indirect approaches, application of certain chiral reagents and chiral stationary phases (though very expensive). Methods of separation of diastereomers of (RS)-baclofen prepared with different chiral derivatizing reagents (under microwave irradiation at ease and in less time) on reversed-phase achiral columns or via a ligand exchange approach providing high-sensitivity detection by the relatively less expensive methods of TLC and HPLC are discussed. The methods may be helpful for determination of enantiomers in biological samples and in pharmaceutical formulations for control of enantiomeric purity and can be practiced both in analytical laboratories and industry for routine analysis and R&D activities.

  17. DEVELOPMENT OF SUSTAINED RELEASE TABLETS CONTAINING SOLID DISPERSIONS OF BACLOFEN

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    K. H. Janardhana

    2015-07-01

    Full Text Available Sustained release tablets containing solid dispersions granules of a poorly water soluble drug were prepared to investigate the controlled release of the drug. Baclofen was chosen because of its poor water solubility and short elimination half-life. Poloxamer 188 and PEG 6000 were used as solid dispersion carrier. Free flowing solid dispersion granules were prepared by adsorbing the melt of the drug and carriers onto the surface of an adsorbent, Carbopol 934P followed by direct compression with HPMC K4M and HPMC K100 to obtain an solid dispersion loaded sustained release tablets. FTIR studies confirmed that the compatibility of drug and carriers. Differential scanning calorimetry (DSC and X-ray diffraction (XRD revealed partially amorphous structures of the drug in solid dispersion granules. The solid dispersion granules dissolved completely within 30 min, which was much faster than that of pure drug baclofen. The sustained release of baclofen from the solid dispersion containing tablet was achieved for 2 h in gastric fluid (pH 1.2 and for up to 10 h in intestinal fluid (pH 6.8. A combination of solid dispersion techniques using adsorption and sustained release concepts is a promising approach to control the release rate of poorly water-soluble drugs.

  18. Reduction of chronic non-specific low back pain: A randomised controlled clinical trial on acupuncture and baclofen

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    Rastqar Ali

    2010-04-01

    Full Text Available Abstract Background Chronic non-specific low back pain (LBP is a prevalent (80% and multi-dimensional illness. This study aims to test whether acupuncture, baclofen, or combined treatment with acupuncture and baclofen alleviates symptoms of non-specific chronic LBP in men. Methods Eight-four (84 men aged 50-60 years with non-specific chronic LBP were randomly assigned to four groups: the baclofen group received only baclofen (30 mg/day; the acupuncture group received only acupuncture at selected acupoints; the acupuncture + baclofen group received combined treatment with acupuncture and baclofen treatments; and the control group received no pain reduction treatment. After five weeks of treatment, visual analogue scale (VAS and self-reported pain disability with the Roland-Morris Disability Questionnaire (RDQ were conducted for outcome measures. Results After treatment, the baclofen, acupuncture and acupuncture + baclofen groups all had lower VAS and RDQ scores. Significantly higher reduction and improvement in VAS and RDQ scores were found in the acupuncture and acupuncture + baclofen groups compared to the baclofen group. Conclusion The present study indicates that the combined treatment of acupuncture and baclofen is more effective than baclofen treatment alone to reduce pain in patients with non-specific chronic LBP. Trial registration number ACTRN12609000698279

  19. Baclofen and NOS inhibitors interact to evoke synergistic hypothermia in rats.

    Science.gov (United States)

    Rawls, Scott M; Jacobs, Kyle; Tallarida, Ronald J

    2006-01-11

    Our laboratory recently demonstrated that a drug combination of baclofen and L-NAME, a nonspecific nitric oxide synthase (NOS) inhibitor, evokes synergistic hypothermia in rats. These data are the first demonstration of synergy between a GABA agonist and NOS inhibitor. While the hypothermic synergy suggests a role for NOS in baclofen pharmacology, it is unclear whether the super-additive hypothermia is specific for baclofen and L-NAME or extends to drug combinations of baclofen and other NOS inhibitors. The site of action (central or peripheral) and isoforms of NOS that mediate the synergy are also unknown. Here, we confirm the hypothermic synergy with additional data and discuss potential mechanisms of the drug interaction. Baclofen (2.5, 3.5, 5 and 7.5 mg/kg, i.p.) was administered to rats by itself or with 7-nitroindazole (7-NI), a neuronal NOS inhibitor. 7-NI (10 mg/kg, i.p.) did not affect body temperature. For combined administration, 7-NI (10 mg/kg, i.p.) increased the relative potency of baclofen (F=18.9, P<0.05). The present data validate the hypothermic synergy caused by the drug combination of baclofen and L-NAME and implicate nNOS in the synergy. In a context broader than thermoregulation, NO production and transmission may play an important role in baclofen pharmacology.

  20. The anti-spasticity drug baclofen alleviates collagen-induced arthritis and regulates dendritic cells.

    Science.gov (United States)

    Huang, Shichao; Mao, Jianxin; Wei, Bin; Pei, Gang

    2015-07-01

    Baclofen is used clinically as a drug that treats spasticity, which is a syndrome characterized by excessive contraction of the muscles and hyperflexia in the central nervous system (CNS), by activating GABA(B) receptors (GABA(B)Rs). Baclofen was recently reported to desensitize chemokine receptors and to suppress inflammation through the activation of GABA(B)Rs. GABA(B)Rs are expressed in various immune cells, but the functions of these receptors in autoimmune diseases remain largely unknown. In this study, we investigated the effects of baclofen in murine collagen-induced arthritis (CIA). Oral administration of baclofen alleviated the clinical development of CIA, with a reduced number of IL-17-producing T helper 17 (T(H)17) cells. In addition, baclofen treatment suppressed dendritic cell (DC)-primed T(H)17 cell differentiation by reducing the production of IL-6 by DCs in vitro. Furthermore, the pharmacological and genetic blockade of GABA(B)Rs in DCs weakened the effects of baclofen, indicating that GABA(B)Rs are the molecular targets of baclofen on DCs. Thus, our findings revealed a potential role for baclofen in the treatment of CIA, as well as a previously unknown signaling pathway that regulates DC function.

  1. A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity

    NARCIS (Netherlands)

    Heetla, H. W.; Proost, J. H.; Molmans, B. H.; Staal, M. J.; van Laar, T.

    2016-01-01

    AimsIntrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic-pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations

  2. Pharmacokinetic Alteration of Baclofen by Multiple Oral Administration of Herbal Medicines in Rats

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    Tae Hwan Kim

    2014-01-01

    Full Text Available The potential pharmacokinetic (PK interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY and Achyranthes bidentata radix (AB extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW, OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42–4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (Cmax and longer time to reach Cmax (Tmax were observed in OY pretreated rats without changes in the area under the curve (AUC and the fraction excreted into urine (Furine. The absorption rate (Ka of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.

  3. INTRATHECAL BACLOFEN OVERDOSE - REPORT OF 7 EVENTS IN 5 PATIENTS AND REVIEW OF THE LITERATURE

    NARCIS (Netherlands)

    DELHAAS, EM; BROUWERS, JRBJ

    1991-01-01

    This study is intended to alert the clinician to the insidious symptoms of baclofen overdose, its prevention and treatment. In a group of 43 patients suffering from previously intractable spasticity and a total treatment time of 2,422 weeks, 7 events of intrathecal baclofen overdose happened in 5 pa

  4. [Identification and quantitative determination of baclofen in human blood by HPLC with mass spectrometry detection].

    Science.gov (United States)

    Dukova, O A; Kotlovsky, M Yu; Pokrovsky, A A; Suvorova, E V; Shivrina, T G; Krasnov, E A; Efremov, A A

    2016-03-01

    A method of identification and quantitative determination of baclofen in blood by HPLC with mass spectrometry detection has been developed. It is characterized by high sensitivity, specificity, linearity, accuracy, reproducibility, and a low detection for quantitative determination. The method has been used for diagnostics of acute baclofen poisoning in patients.

  5. Population Pharmacokinetics of Oral Baclofen in Pediatric Patients with Cerebral Palsy

    Science.gov (United States)

    He, Yang; Brunstrom-Hernandez, Janice E.; Thio, Liu Lin; Lackey, Shellie; Gaebler-Spira, Deborah; Kuroda, Maxine M.; Stashinko, Elaine; Hoon, Alexander H.; Vargus-Adams, Jilda; Stevenson, Richard D.; Lowenhaupt, Stephanie; McLaughlin, John F.; Christensen, Ana; Dosa, Nienke P.; Butler, Maureen; Schwabe, Aloysia; Lopez, Christina; Roge, Desiree; Kennedy, Diane; Tilton, Ann; Krach, Linda E.; Lewandowski, Andrew; Dai, Hongying; Gaedigk, Andrea; Leeder, J. Steven; Jusko, William J.

    2014-01-01

    Objective To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use. Subjects design Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland). Results R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children. Conclusion The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age. PMID:24607242

  6. GABAB receptor as therapeutic target for drug addiction: from baclofen to positive allosteric modulators

    Directory of Open Access Journals (Sweden)

    Roberta Agabio

    2015-04-01

    Full Text Available The present paper summarizes experimental and clinical data indicating the therapeutic potential of the GABAB receptor agonist, baclofen, in the treatment of alcohol use disorder (AUD and substance use disorder (SUD. Multiple preclinical studies have demonstrated the ability of baclofen to suppress alcohol drinking (including binge- and relapse-like drinking, oral alcohol self-administration, and intravenous self-administration of cocaine, nicotine, amphetamine, methamphetamine, morphine, and heroin in rodents. Some randomized, controlled trials (RCTs and case reports support the efficacy of baclofen in suppressing alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. Data from RCTs and open studies investigating baclofen efficacy on SUD are currently less conclusive. Interest in testing high doses of baclofen in AUD and SUD treatment has recently emerged. Preclinical research has extended the anti-addictive properties of baclofen to positive allosteric modulators of the GABAB receptor (GABAB PAMs. In light of their more favourable side effect profile (compared to baclofen, GABAB PAMs may represent a major step forward in a GABAB receptor-based pharmacotherapy of AUD and SUD.

  7. [GABAB receptor as therapeutic target for drug addiction: from baclofen to positive allosteric modulators].

    Science.gov (United States)

    Agabio, Roberta; Colombo, Giancarlo

    2015-01-01

    The present paper summarizes experimental and clinical data indicating the therapeutic potential of the GABAB receptor agonist, baclofen, in the treatment of alcohol use disorder (AUD) and substance use disorder (SUD). Multiple preclinical studies have demonstrated the ability of baclofen to suppress alcohol drinking (including binge- and relapse-like drinking), oral alcohol self-administration, and intravenous self-administration of cocaine, nicotine, amphetamine, methamphetamine, morphine, and heroin in rodents. Some randomized, controlled trials (RCTs) and case reports support the efficacy of baclofen in suppressing alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. Data from RCTs and open studies investigating baclofen efficacy on SUD are currently less conclusive. Interest in testing high doses of baclofen in AUD and SUD treatment has recently emerged. Preclinical research has extended the anti-addictive properties of baclofen to positive allosteric modulators of the GABAB receptor (GABAB PAMs). In light of their more favourable side effect profile (compared to baclofen), GABAB PAMs may represent a major step forward in a GABAB receptor-based pharmacotherapy of AUD and SUD.

  8. Asymmetric Transfer Hydrogenation to Synthesize R-(-)-Baclofen%不对称氢转移合成R-(-)-Baclofen

    Institute of Scientific and Technical Information of China (English)

    许波洪; 张跃

    2010-01-01

    以外消旋的β-羟基酮酸酯为原料,通过不对称氢转移的方法,高效的合成了光学活性的手性中间体β-羟基酮酸酯,光学纯度达到98%,然后通过亲核取代反应生成了光学活性的β-氰基丙酮酸酯,最后还原生成R-(-)-Baclofen.

  9. Status dystonicus resembling the intrathecal baclofen withdrawal syndrome: a case report and review of the literature

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    Muirhead William

    2010-08-01

    Full Text Available Abstract Introduction Status dystonicus is a rare but life-threatening disorder characterized by increasingly frequent and severe episodes of generalized dystonia that may occur in patients with primary or secondary dystonia. Painful and repetitive spasms interfere with respiration and may cause metabolic disturbances such as hyperpyrexia, dehydration, respiratory insufficiency, and acute renal failure secondary to rhabdomyolysis. Intrathecally administered baclofen, delivered by an implantable pump system, is widely used for the treatment of refractory spasticity. Abrupt cessation of intrathecal baclofen infusion has been associated with a severe withdrawal syndrome comprised of dystonia, autonomic dysfunction, hyperthermia, end-organ failure and sometimes death. The aetiology of this syndrome is not well understood. Status dystonicus describes the episodes of acute and life-threatening generalized dystonia, which occasionally manifest themselves in patients with dystonic syndromes. Case presentation We present the case of a nine-year-old Caucasian boy who experienced a severe episode of status dystonicus with no known cause and clinical features resembling those described in intrathecal baclofen withdrawal. Our patient subsequently underwent the placement of an intrathecal baclofen pump without incident. Conclusion The similarity between the clinical features of the case we present and those reported in connection to abrupt withdrawal of intrathecal baclofen is emphasized. Several drugs, although not intrathecal baclofen withdrawal, have previously been associated with status dystonicus. The similarity between the life-threatening dystonic episode experienced by our patient, and those reported in intrathecal baclofen withdrawal, highlights the possibility that, rather than representing a true physiological withdrawal syndrome, abrupt withdrawal of intrathecal baclofen may simply precipitate an episode of status dystonicus in susceptible

  10. FORMULATION AND EVALUATION OF BACLOFEN CONTROLLED POROSITY OSMOTIC PUMP TABLETS

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    Indarapu Rajendra Prasad

    2013-06-01

    Full Text Available In the present study, attempts were made to develop and evaluate the controlled porosity osmotic pump (CPOP based drug delivery system of sparingly water soluble drug Baclofen. Formulation variables, such as, levels of solubility enhancer, ratio of drug to osmogents, coat thickness of semi permeable membrane (SPM and level of pore former were found to affect the drug release from the developed formulations. Cellulose acetate was used as the semi permeable membrane. Drug release was directly proportional to the level of the solubility enhancer, osmotic pressure generated by osmotic agent and level of pore former; however, was inversely proportional to the coat thickness of SPM. Drug release from developed formulations was independent of pH and agitation intensities of release media. Burst strength of the exhausted shells decreased with increase in the level of pore former. This system was found to deliver Baclofen at a zero-order rate. The optimized formulations were subjected to stability studies as per ICH guidelines, and formulations were found to be stable after 45days study.

  11. Structural characterization and Hirshfeld surface analysis of racemic baclofen

    Science.gov (United States)

    Maniukiewicz, Waldemar; Oracz, Monika; Sieroń, Lesław

    2016-11-01

    The crystal structure of baclofen, (R,S) [4-amino-3-(4-chlorophenyl)butanoic acid], (C10H12ClNO2, Mr = 213.66) has been determined by single crystal X-ray diffraction analysis. The title compound crystallizes in the orthorhombic space group Pbca (No. 61) with a = 9.2704(5), b = 7.0397(4), c = 30.4015(15) Å, V = 1984.0(2) Å3 and Z = 8. The molecules exist as zwitterions, adopting a gauche conformation with respect to the Cαsbnd Cβ bond, and held in a cross-linked chain arrangement by strong Nsbnd H⋯O hydrogen bonds and Csbnd Cl⋯π interactions. The electrostatic molecular potential as well as the intermolecular interactions of the title compound were analyzed by the Hirshfeld surfaces. The FT-IR spectrum is also reported. The DTA, TG and DTG results indicate that baclofen is stable up to 205 °C.

  12. PREPARATION AND IN-VITRO EVALUATION OF BACLOFEN LOADED MICROSPHERES

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    Polepalle Madhulatha

    2012-09-01

    Full Text Available The present study was aimed to prepare Baclofen microspheres for sustained release using various polymers such as ethyl cellulose (hydrophobic, hydroxy propyl methyl cellulose (hydrophilic by employing solvent evaporation technique. Drug and excipients compatibility was studied by Fourier Transform Infrared Spectroscopy and no incompatibility was observed. The obtained microspheres were evaluated for the percent drug content, entrapment efficiency and in-vitro dissolution studies. The entrapment efficiency of the obtained formulations was in between 66-88% and in-vitro release of F7 formulation showed 93% in 24 hrs. Scanning Electron Microscopy, Differential Scanning Calorimetry and X-Ray Diffraction studies were performed for F7 formulation. From the results Scanning Electron Microscopy of reveals that microspheres was found in spherical and porous nature. X-Ray Diffraction studies results showed baclofen was in amorphous form which was further confirmed by Differential Scanning Calorimetry. The curve fitting data revealed that the release of obtained formulations follows mixed order kinetics with non‐fickian type of drug release (anomalous.

  13. Treatment of motor and behavioural symptoms in three Lesch-Nyhan patients with intrathecal baclofen.

    Science.gov (United States)

    Pozzi, Marco; Piccinini, Luigi; Gallo, Maurizio; Motta, Francesco; Radice, Sonia; Clementi, Emilio

    2014-12-12

    Current therapies for the Lesch-Nyhan Syndrome (OMIM: 300322) are off-label and experimental, often leading to inconsistent outcomes. We here report the effects of an intrathecal baclofen therapy, carried out at the Scientific Institute Eugenio Medea (Lecco, Italy), on three patients who no longer received benefit from previous therapies. This treatment, as expected, ameliorated the motor symptoms and, unexpectedly, it also improved behavioural components. This result may involve a functional interaction between baclofen and dopamine, complemented by an anxiolytic effect. Our observations provide the rationale for the use of intrathecal baclofen administration in the therapy of the Lesch-Nyhan Syndrome.

  14. L-baclofen-sensitive GABAB binding sites in the medial vestibular nucleus localized by immunocytochemistry

    Science.gov (United States)

    Holstein, G. R.; Martinelli, G. P.; Cohen, B.

    1992-01-01

    L-Baclofen-sensitive GABAB binding sites in the medial vestibular nucleus (MVN) were identified immunocytochemically and visualized ultrastructurally in L-baclofen-preinjected rats and monkeys, using a mouse monoclonal antibody with specificity for the p-chlorophenyl moiety of baclofen. Saline-preinjected animals showed no immunostain. In drug-injected animals, there was evidence for both pre- and postsynaptic GABAergic inhibition in MVN mediated by GABAB receptors. These neural elements could be utilized in control of velocity storage in the vestibulo-ocular reflex.

  15. [Temporary recommendation for use on off-label baclofen: viewpoint of Prescribers of the CAMTEA system].

    Science.gov (United States)

    Rolland, Benjamin; Deheul, Sylvie; Danel, Thierry; Bence, Camille; Blanquart, Marie-Christine; Bonord, Alexandre; Semal, Robin; Briand, Thierry; Sochala, Michel; Dubocage, Christelle; Dupriez, François; Duquesne, Damien; Gibour, Bernard; Loosfeld, Xavier; Henebelle, Dorothée; Henon, Michael; Vernalde, Elodie; Matton, Christian; Bacquet, Jean-Eudes; Molmy, Lucie; Sarasy, François; Simioni, Nicolas; Richez, Cécile; Gentil-Spinosi, Laure; Vosgien, Véronique; Yguel, Jacques; Ledent, Thierry; Auffret, Marine; Wilquin, Maroussia; Ziolkowski, Danièle; Sochala, Michel; Gautier, Sophie; Bordet, Régis; Cottencin, Olivier

    2015-01-01

    The use of high dose baclofen for alcohol-dependence emerged in France from 2008 based on empirical findings, and is still off-label. However, due to the rapid increase in this prescribing practice, the French health authorities have decided to frame it using an extraordinary regulatory measure named "temporary recommendation for use" (TRU). Baclofen prescribers from CAMTEA, a regional team-based off-label system for supervising baclofen prescribing, which was developed much prior to the TRU, discuss herein the pros and cons of this measure and the applicability of its different aspects in the daily clinical practice.

  16. Inhibition of calcium currents in cultured rat dorsal root ganglion neurones by (-)-baclofen.

    OpenAIRE

    Dolphin, A C; Scott, R.H.

    1986-01-01

    Voltage-dependent inward calcium currents (ICa) activated in cultured rat dorsal root ganglion neurones were reversibly reduced in a dose-dependent manner by (-)-baclofen (10 microM to 100 microM). Baclofen (100 microM) reduced the calcium-dependent slow outward potassium current (IK(Ca)). This current was abolished in calcium-free medium and by 300 microM cadmium chloride. The action of baclofen on IK(Ca) was reduced when the calcium concentration in the medium was increased from 5 mM to 30 ...

  17. Gambling disorder: a side effect of an off-label prescription of baclofen-literature review.

    Science.gov (United States)

    Guillou-Landreat, Morgane; Victorri Vigneau, Caroline; Gerardin, Marie

    2017-01-10

    The use of high-dose baclofen emerged in 2008 in the treatment of alcohol-use disorders. Its prescription is still off-label in France, but recent trials have suggested the interest of using high doses for alcohol dependence, so we have to deal with an increase in its use. However, we still have few data about the adverse effects of a high-dose baclofen prescription, especially in complex addictive disorders. We present a case of a 32-year-old man who sought treatment for gambling disorders (GDs). He had complex addictive disorders, including alcohol-use disorders and GDs. He developed a severe GD, after treatment with a high dose of baclofen. The maximum dose was 160 mg/day, prescribed for his alcohol-use disorders. According to the Naranjo algorithm, the score was +7, it enabled to conclude that problem of gambling was probably imputable to baclofen. We discuss this case with reference to literature.

  18. Baclofen in the short-term maintenance treatment of benzodiazepine dependence.

    Science.gov (United States)

    Shukla, Lekhansh; Kandasamy, Arun; Kesavan, Muralidharan; Benegal, Vivek

    2014-11-01

    Benzodiazepine (BZD) dependence is a significant public health problem. Apart from the long-term tapering doses of BZD, no others drugs are available for the maintenance treatment of BZD dependence. Baclofen has been used in alcohol and other drug dependence as long-term anti-craving agent. Since alcohol and BZD act through the GABA receptor, we attempted to study the effect of Baclofen as maintenance treatment in a series of five cases with BZD dependence.

  19. Selective Effects of Baclofen on Use-Dependent Modulation of GABAB Inhibition after Tetraplegia

    OpenAIRE

    Barry, Melissa D.; Bunday, Karen L.; Chen, Robert; Perez, Monica A.

    2013-01-01

    Baclofen is a GABAB receptor agonist commonly used to relief spasticity related to motor disorders. The effects of baclofen on voluntary motor output are limited and not yet understood. Using noninvasive transcranial magnetic and electrical stimulation techniques, we examined electrophysiological measures probably involving GABAB (long-interval intracortical inhibition and the cortical silent period) and GABAA (short-interval intracortical inhibition) receptors, which are inhibitory effects m...

  20. Baclofen in the short-term maintenance treatment of benzodiazepine dependence

    Directory of Open Access Journals (Sweden)

    Lekhansh Shukla

    2014-01-01

    Full Text Available Benzodiazepine (BZD dependence is a significant public health problem. Apart from the long-term tapering doses of BZD, no others drugs are available for the maintenance treatment of BZD dependence. Baclofen has been used in alcohol and other drug dependence as long-term anti-craving agent. Since alcohol and BZD act through the GABA receptor, we attempted to study the effect of Baclofen as maintenance treatment in a series of five cases with BZD dependence.

  1. Clinical effectiveness of baclofen for the treatment of alcohol dependence: a review

    Directory of Open Access Journals (Sweden)

    Brennan JL

    2013-07-01

    Full Text Available Jessica L Brennan,2 Jonathan G Leung,1 Jane P Gagliardi,3 Sarah K Rivelli,3 Andrew J Muzyk4 1Department of Hospital Pharmacy Services, Mayo Clinic, Rochester, MN, 2Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, 3Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, 4Department of Pharmacy Practice, Campbell University School of Pharmacy and Health Sciences, Buies Creek, NC, USA Abstract: Baclofen, an agonist at the B subunit of gaba-aminobutyric acid receptor, possesses pharmacologic properties that may confer utility for the treatment of alcohol dependence. Research suggests that not only can it be useful in promoting maintenance of alcohol abstinence but also it may play a key role in decreasing alcohol cravings and anxiety often associated with alcohol dependence. To assess the benefit of baclofen for alcohol dependence, a review of the literature was conducted to identify published data investigating this off-label treatment. Four randomized controlled trials to date have been published and were included in this review. Although primary outcomes differ between studies, patients randomized to baclofen experience higher rates of abstinence from alcohol than those taking placebo in two of the trials. Secondary analyses indicate that baclofen is safe in patients with alcohol dependence, including those with moderate to severe liver cirrhosis, and may provide beneficial anxiolytic effects. Despite some positive data, the largest available randomized controlled trial failed to find any differences between baclofen and placebo. In all studies, individuals with severe medical comorbidities, seizure disorders, and psychiatric disorders were excluded from trials, which may limit external validity. In summary, there may be beneficial effects from using baclofen for the treatment of alcohol dependence; however, limited conclusions can be drawn from the small number of studies

  2. Cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated alcohol-withdrawal syndrome

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    Vikram K Reddy

    2014-01-01

    Full Text Available Objectives: Benzodiazepines (BZDs are the first-line drugs in alcohol-withdrawal syndrome (AWS. Baclofen, a gamma-aminobutyric acid B (GABA B agonist, controls withdrawal symptoms without causing significant adverse effects. The objective of this study was to compare the cost-effectiveness of baclofen and chlordiazepoxide in the management of uncomplicated AWS. Materials and Methods : This was a randomized, open label, standard controlled, parallel group study of cost-effectiveness analysis (CEA of baclofen and chlordiazepoxide in 60 participants with uncomplicated AWS. Clinical efficacy was measured by the Clinical Institute Withdrawal Assessment for alcohol (CIWA-Ar scores. Lorazepam was used as supplement medication if withdrawal symptoms could not be controlled effectively by the study drugs alone. Both direct and indirect medical costs were considered and the CEA was analyzed in both patient′s perspective and third-party perspective. Results : The average cost-effectiveness ratio (ACER in patient′s perspective of baclofen and chlordiazepoxide was Rs. 5,308.61 and Rs. 2,951.95 per symptom-free day, respectively. The ACER in third-party perspective of baclofen and chlordiazepoxide was Rs. 895.01 and Rs. 476.29 per symptom-free day, respectively. Participants on chlordiazepoxide had more number of symptom-free days when compared with the baclofen group on analysis by Mann-Whitney test (U = 253.50, P = 0.03. Conclusion : Both study drugs provided relief of withdrawal symptoms. Chlordiazepoxide was more cost-effective than baclofen. Baclofen was relatively less effective and more expensive than chlordiazepoxide.

  3. The release and transdermal penetration of baclofen formulated in a poloxamer lecithin organogel.

    Science.gov (United States)

    Arnold, John J; Asbill, Scott

    2009-01-01

    The purpose of this study was to evaluate the in vitro release and ex vivo penetration of baclofen following incorporation into a 2% poloxamer lecithin organogel. Franz cells were utilized for both the release and penetration studies. Semi-permeable dialysis membranes were used as the model skin for the penetration study. Baclofen release and penetration at predetermined time points were assessed using high-performamce liquid chromatographic analysis. Results demonstrated that baclofen release from the poloxamer lecithin organogel was significantly higher than its penetration through porcine skin. The amount of baclofen released by the poloxamer lecithin organogel was linear up to 12 hours. Approximately 20% of applied drug was released over the duration of the study period. In comparison with drug released, the ex vivo penetration of baclofen through porcine skin was very low with only minute detectable quantities (significantly less than 1%) after the 12-hour study period. These results suggest that the request to include baclofen into a compounded poloxamer lecithin organogel should be approached cautiously by compounding pharmacists.

  4. Baclofen pump catheter leakage after migration of the abdominal catheter in a pediatric patient with spasticity.

    Science.gov (United States)

    Dastgir, Amer; Ranalli, Nathan J; MacGregor, Theresa L; Aldana, Philipp R

    2015-09-01

    The authors report an unusual case of intrathecal baclofen withdrawal due to the perforation and subsequent leakage of a baclofen pump catheter in a patient with spastic cerebral palsy. A 15-year-old boy underwent an uncomplicated placement of an intrathecal baclofen pump for the treatment of spasticity due to cerebral palsy. After excellent control of symptoms for 3 years, the patient presented to the emergency department with increasing tremors following a refill of his baclofen pump. Initial evaluation consisted of radiographs of the pump and catheter, which appeared normal, and a successful aspiration of CSF from the pump's side port. A CT dye study revealed a portion of the catheter directly overlying the refill port and extravasation of radiopaque dye into the subfascial pocket anterior to the pump. During subsequent revision surgery, a small puncture hole in the catheter was seen to be leaking the drug. The likely cause of the puncture was an inadvertent perforation of the catheter by a needle during the refilling of the pump. This case report highlights a unique complication in a patient with an intrathecal baclofen pump. Physicians caring for these patients should be aware of this rare yet potential complication in patients presenting with baclofen withdrawal symptoms.

  5. A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers.

    Science.gov (United States)

    Agarwal, Suresh K; Kriel, Robert L; Cloyd, James C; Coles, Lisa D; Scherkenbach, Lisa A; Tobin, Michael H; Krach, Linda E

    2015-01-01

    Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures.

  6. Increased spasticity from a fracture in the baclofen catheter caused by Charcot spine: case report.

    Science.gov (United States)

    Ravindra, Vijay M; Ray, Wilson Z; Sayama, Christina M; Dailey, Andrew T

    2015-04-01

    In patients with Charcot spine, a loss of normal feedback response from the insensate spine results in spinal neuropathy. Increasing deformity, which can manifest as sitting imbalance, crepitus, or increased back pain, can result. We present the case of a patient with a high-thoracic spinal cord injury (SCI) who subsequently developed a Charcot joint at the T10-11 level that resulted in a dramatic increase in previously controlled spasticity after fracture of an existing baclofen catheter. The 68-year-old man with T4 paraplegia presented with increasing baclofen requirements and radiographic evidence of fracture of the intrathecal baclofen catheter with an associated Charcot joint with extensive bony destruction. The neuropathic spinal arthropathy caused mechanical baclofen catheter malfunction and resulting increased spasticity. The patient was found to have transected both his spinal cord and the baclofen catheter. Treatment consisted of removal of the catheter and stabilization with long-segment instrumentation and fusion from T6 to L2. Follow-up radiographs obtained a year and a half after surgery showed no evidence of hardware failure or significant malalignment. The patient has experienced resolution of symptoms and does not require oral or intrathecal baclofen. This is the only reported case of a Charcot spine causing intrathecal catheter fracture, leading to increased spasticity. This noteworthy case suggests that late spinal instability should be considered in the setting of SCI and increased spasticity.

  7. Bruxism Associated with Anoxic Encephalopathy: Successful Treatment with Baclofen

    Science.gov (United States)

    Janati, A. Bruce; ALGhasab, Naif Saad; ALGhassab, Fahad Saad

    2013-01-01

    Introduction. Bruxism is a movement disorder characterized by grinding and clenching of the teeth. Etiology of bruxism can be divided into three groups: psychosocial factors, peripheral factors, and pathophysiological factors. Methods. The clinical investigation was conducted at King Khaled Hospital in Hail, Saudi Arabia, in 2012. Results. A 16-year-old Saudi female was brought to the hospital in a comatose state and with generalized convulsive seizures secondary to acute anoxic encephalopathy. In the third week of hospitalization, while still in a state of akinetic mutism, she developed incessant bruxism which responded favorably to a GABA receptor agonist (baclofen). Conclusion. Our data support the hypothesis that bruxism emanates from imbalance or dysregulation of the neurotransmitter system. Larger scale studies will be needed to confirm this hypothesis. PMID:24455317

  8. Bruxism Associated with Anoxic Encephalopathy: Successful Treatment with Baclofen

    Directory of Open Access Journals (Sweden)

    A. Bruce Janati

    2013-01-01

    Full Text Available Introduction. Bruxism is a movement disorder characterized by grinding and clenching of the teeth. Etiology of bruxism can be divided into three groups: psychosocial factors, peripheral factors, and pathophysiological factors. Methods. The clinical investigation was conducted at King Khaled Hospital in Hail, Saudi Arabia, in 2012. Results. A 16-year-old Saudi female was brought to the hospital in a comatose state and with generalized convulsive seizures secondary to acute anoxic encephalopathy. In the third week of hospitalization, while still in a state of akinetic mutism, she developed incessant bruxism which responded favorably to a GABA receptor agonist (baclofen. Conclusion. Our data support the hypothesis that bruxism emanates from imbalance or dysregulation of the neurotransmitter system. Larger scale studies will be needed to confirm this hypothesis.

  9. Baclofen for alcohol dependence in France: incidence of treated patients and prescription patterns--a cohort study.

    Science.gov (United States)

    Dupouy, Julie; Fournier, Jean-Pascal; Jouanjus, Émilie; Palmaro, Aurore; Poutrain, Jean-Christophe; Oustric, Stéphane; Lapeyre-Mestre, Maryse

    2014-02-01

    Recently, baclofen has been widely promoted for treatment of alcohol dependence in France. Our aim was firstly to describe the incidence of patients newly treated with baclofen for alcohol dependence in France from 2007 to 2011, and secondly to describe baclofen prescription patterns and prescribers. A retrospective cohort study of patients newly treated with baclofen was conducted using the "Echantillon Généraliste des Bénéficiaires" database (EGB). Patients with a first dispensation of baclofen between 01/01/2007 and 31/12/2011, followed by a second in the next 120 days, were included. Patients were considered treated with baclofen for neurological conditions if at least one of the following conditions was found to be true: (1) presence of a neurological condition for which baclofen could be prescribed, (2) dispensation of dantrolene, another anti-spastic drug, or (3) hospitalization for a neurological condition for which baclofen could be prescribed. We assumed that all the remaining patients were treated for alcohol dependence. During the 5-year period, 676 patients were incident users. While the annual incidence rate of patients newly treated with baclofen for neurological conditions remained stable, the annual incidence rate of patients newly treated with baclofen for alcohol dependence increased by a factor of 2.9 between 2007 (0.09/1000 person-years) and 2011 (0.26/1000 person-years). In the alcohol dependence group, median duration of baclofen treatment was 143.5 [74.0; 377.0] days; median daily dose was 24.4 [14.8; 39.5] mg. This study demonstrated the rapidly increasing use of baclofen in France for treatment of alcohol dependence.

  10. Once daily baclofen sustained release or gastro-retentive system are acceptable alternatives to thrice daily baclofen immediate release at same daily dosage in patients

    Directory of Open Access Journals (Sweden)

    Sampat Nitin

    2009-01-01

    Full Text Available Background: Baclofen, a GABA-agonist, is currently available as an immediate release (IR formulation for relieving neurogenic spasticity in a variety of disorders. Baclofen IR requires to be administered three times a day which inadvertently increases the chances of medication noncompliance among patients and is also associated with side effects such as drowsiness and muscle weakness. Aim: To overcome the shortcomings of baclofen IR, two modified formulations, baclofen sustained release (SR and gastric retentive system (GRS, have been proposed to be equivalent in efficacy to baclofen IR with the administration of a single daily dose. Materials and Methods: Ninety patients with chronic neurogenic muscular spasticity were enrolled requiring 10-20 mg of baclofen IR every eight hours. The patients were randomized to two treatment arms: SR (n = 46 or GRS (n = 44 at the same once-daily dose for four weeks. Efficacy was measured by Ashworth score for muscle tone, spasm score, reflex score, 30-item functional independence score, and patient′s diary score for three most affected activities of daily life. Results: The mean Ashworth score changed significantly (P = 0.00 for patients in the SR group from 3.03-2.69 (-0.35 and 3.07-2.70 (-0.37 for patients in the GRS group. There was no significant difference (P = 0.87 between baseline-adjusted Ashworth score reductions on SR (-0.35 and GRS (-0.37. Similar results were obtained for spasm, reflex, and functional independence scores. The mean baseline-adjusted patient-diary scores did not differ significantly between 8 am, 12 pm, 4 pm, and 8 pm (P = 0.96, either on SR (-5.3 to -6.1 or GRS (-7.3 to -8.1, indicating a uniform effect round-the-day on both. Further, sedation scores (mean ± SEM decreased significantly (P < 0.05 on both SR (10.36 ± 1.37 to 6.18 ± 0.92 and GRS (8.14 ± 1.57 to 5.33 ± 1.11, suggesting better toleration. Conclusion: Once-daily baclofen SR and GRS are efficacious, convenient, and

  11. Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption.

    Science.gov (United States)

    Kasten, Chelsea R; Blasingame, Shelby N; Boehm, Stephen L

    2015-02-01

    The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides "binge-like" ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24-h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(-)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(-)-baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature.

  12. Baclofen blocks yohimbine-induced increases in ethanol-reinforced responding in rats.

    Science.gov (United States)

    Williams, Keith L; Nickel, Melissa M; Bielak, Justin T

    2016-05-01

    Chronic or repeated stress increases alcohol consumption. The GABA-B agonist baclofen decreases alcohol consumption and may be most effective for individuals with comorbid anxiety/stress disorders. The present study sought to determine if baclofen blocks stress-induced increases in ethanol self-administration as modeled by repeated yohimbine injections in rats. Rats were trained to respond for 15% w/v ethanol in operant chambers using a method that applies neither water deprivation nor saccharin/sucrose fading. Following training, the rats received 6 injections of 1.25mg/kg yohimbine were given immediately prior to the operant sessions during a 2-week time period. Subsequently, some rats were pair-matched to receive either 1.25mg/kg yohimbine or saline in the presence of 0.3, 1, and 3mg/kg baclofen prior to sessions. Acquisition of ethanol self-administration was poor. Pretreatment with yohimbine consistently increased responding across repeated injections. Yohimbine's effect on ethanol intake unexpectedly diverged from the effect on responding as the rats failed to consume all reinforcers earned. Smaller doses of baclofen paired with saline injections had no effect on ethanol responding; only 3mg/kg baclofen reduced ethanol self-administration. The smallest baclofen dose of 0.3mg/kg failed to block the yohimbine-induced increase in self-administration. The large baclofen dose of 3mg/kg continued to suppress ethanol self-administration when given with yohimbine. Baclofen 1mg/kg blocked the effect of yohimbine even though it had no effect when given in the absence of yohimbine. Exposure to high ethanol concentrations may induce self-administration only in certain conditions. The dissociation between responding and intake suggests that repeated yohimbine injections may initiate other behavioral or physiological mechanisms that confound its effects as a pharmacological stressor. Furthermore, an optimal baclofen dose range may specifically protect against stress

  13. Effect of Gabapentin and Baclofen on Histology Study in Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Fifteen A. Fajrin

    2015-12-01

    Full Text Available Neuropathic pain resulted from injury to nerves is often resistant to current treatments and can seriously cause chronic pain if no appropriate treatment is given. This study was designed to prove the effectiveness of gabapentin and baclofen in increasing latency time toward thermal stimulus and recovering the morphology of dorsal horn of spinal cord in neuropathic-induced chronic pain. Forty mice were divided into 8 groups i.e sham, negative control, gabapentin at three different doses (10, 30, 100 nmol and baclofen at three different doses (1, 10, 30 nmol. Neuropathic condition was induced by ligation of sciatic nerve with Partial Sciatic Nerve Ligation (PSNL method. Gabapentin and baclofen were administrated intrathecally once a day for seven days, a week after neuropathic induction. Latency time toward thermal stimulus was measured on days 0, 1, 3, 5, 7, 8, 10, 12 and 14 after induction. Histology of the dorsal horn of spinal cord tissue was examined by haematoxylline-eosin staining. The results showed that intrathecal injection of gabapentin and baclofen significantly increased latency time of mice toward thermal stimulus compared with negative control. Gabapentin and baclofen are effective as treatment for neuropathic pain. They can also help the recovery process of the histology in dorsal horn in neuropathic pain.

  14. Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues.

    Science.gov (United States)

    Young, Kimberly A; Franklin, Teresa R; Roberts, David C S; Jagannathan, Kanchana; Suh, Jesse J; Wetherill, Reagan R; Wang, Ze; Kampman, Kyle M; O'Brien, Charles P; Childress, Anna Rose

    2014-04-02

    Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen-a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals-could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p baclofen may inhibit the earliest type of drug cue-induced motivational processing-that which occurs outside of awareness-before it evolves into a less manageable state.

  15. Baclofen Induced Encephalopathy in a 6-Year-Old Boy with Advanced Renal Failure

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    Majid MALAK

    2015-06-01

    Full Text Available How to Cite This Article: Malak M, Barzgar M. Baclofen Induced Encephalopathy in a 6-Year-Old boy with Advanced Renal Failure. Iran J Child Neurol. Spring 2015;9(2:61-63. AbstractBaclofen is a drug for many diseases for all ages, but it is hazardous in patients with renal failure. This article talks about a case of baclofen overdose in a child with renal failure.A 6-year-old boy admitted to the emergency department with a loss of consciousness, hypotonia, and areflexia following administration of 20 mg baclofen (1mg/kg/daily in total dose for his voiding dysfunction. His laboratory tests showed advanced renal failure. After withholding the medication andsupportive therapy, he recovered completely after two days. After arousal, he complained of insomnia, strange sensations on the skin, intentional tremors, and ataxia. He left the hospital in good condition in three days.Renal function control before baclofen administration is mandatory especially in high-risk groups. A total dose of 1mg/kg lead to encephalopathy in children with advanced renal failure, with subtle persistent complaints persist are often overlooked for a while.

  16. The effect of baclofen and diazepam on motor skill acquisition in healthy subjects

    DEFF Research Database (Denmark)

    Willerslev-Olsen, Maria; Lundbye-Jensen, Jesper; Petersen, Tue Hvass

    2011-01-01

    Antispastic medication is often used in the clinic together with physiotherapy. However, some of the antispastic drugs, e.g., baclofen and diazepam, may influence the plastic mechanisms that are necessary for motor learning and hence efficient physiotherapy. In the present study, we consequently...... investigated the influence of baclofen and diazepam on acquisition of a visuomotor skill. The study was designed as a semi-randomized, double-blinded, placebo-controlled, crossover study in 16 healthy human subjects. The motor skill task required the subjects to match a given force trajectory by increasing...... that diazepam and baclofen interfere with the acquisition of a motor skill by disrupting some of the neuroplastic changes that are involved in improved motor performance. This suggests that antispastic treatment should be used with caution in subjects receiving concomitant physiotherapy....

  17. How a Drug Shortage Contributed to a Medication Error Leading to Baclofen Toxicity in an Infant.

    Science.gov (United States)

    Lau, Bonnie; Khazanie, Uma; Rowe, Emily; Fauman, Karen

    2016-01-01

    We report the case of a 4-month-old girl who developed encephalopathy, seizures, and respiratory compromise as a result of baclofen toxicity. After some investigation, the accidental ingestion of baclofen was caused by an error in compounding the patient's prescribed omeprazole with baclofen rather than sodium bicarbonate at a retail pharmacy. This error occurred because these two drugs, which were available as powders, were located side by side on the pharmacy shelf. The pharmacist further reported that their normal practice was to use injectable sodium bicarbonate rather than powder to compound an omeprazole suspension; however, the injectable form was not available due to a national shortage. This report demonstrates how a drug shortage contributed to severe clinical consequences and intensive care hospitalization of a patient. It also highlights the need for system improvement to minimize drug shortages.

  18. Self-induced drug intoxication in baclofen: of the calm hypotonic coma in the status epilepticus.

    Science.gov (United States)

    Thill, Chloé; Di Constanzo, Laurence; Pessey, François; Aries, Philippe; Montelescaut, Étienne; Sapin, Jeanne; Vaillant, Catherine; Drouillard, Isabelle

    2016-06-01

    Baclofen is an agonist of peripheral and central B gamma-aminobutyric acid receptors, whose activation causes a myorelaxation and a powerfull depression of the central nervous system. Moreover, it has an action against addiction, in reducing craving. Commercialized since 1975 in France, to control muscle spasticity due to medullar affection or multiple sclerosis, it receives a temporary recommendation of use in march 2014, as a last-line adjuvant treatment in alcohol withdrawal. Beyond its therapeutic use, baclofen is involved in many self-induced intoxications. We report the case of a patient who develops, after a massive ingestion of baclofen (supposed dose ingested: 1 200 mg), a hypotonic and calm coma, requiring her admission in our intensive care unit, and then a status epilepticus.

  19. Effects of "in vivo" administration of baclofen on rat renal tubular function.

    Science.gov (United States)

    Donato, Verónica; Pisani, Gerardo Bruno; Trumper, Laura; Monasterolo, Liliana Alicia

    2013-09-05

    The effects of the in vivo administration of baclofen on renal tubular transport and aquaporin-2 (AQP2) expression were evaluated. In conscious animals kept in metabolic cages, baclofen (0.01-1mg/kg, s.c.) induced a dose-dependent increment in the urine flow rate (UFR) and in sodium and potassium excretion, associated with an increased osmolal clearance (Closm), a diminished urine to plasma osmolality ratio (Uosm/Posm) and a decrease in AQP2 expression. The above mentioned baclofen effects on functional parameters were corroborated by using conventional renal clearance techniques. Additionally, this model allowed the detection of a diminution in glucose reabsorption. Some experiments were performed with water-deprived or desmopressin-treated rats kept in metabolic cages. Either water deprivation or desmopressin treatment decreased the UFR and increased the Uosm/Posm. Baclofen did not change the Uosm/Posm or AQP2 expression in desmopressin-treated rats; but it increased the UFR and diminished the Uosm/Posm and AQP2 expression in water-deprived animals. These results indicate that in vivo administration of baclofen promotes alterations in proximal tubular transport, since glucose reabsorption was decreased. The distal tubular function was also affected. The increased Closm indicates an alteration in solute reabsorption at the ascending limb of the Henle's loop. The decreased Uosm/Posm and AQP2 expression in controls and in water-deprived, but not in desmopressin-treated rats, lead us to speculate that some effect of baclofen on endogenous vasopressin availability could be responsible for the impaired urine concentrating ability, more than any disturbance in the responsiveness of the renal cells to the hormone.

  20. Effect of baclofen on the acid pocket at the gastroesophageal junction.

    Science.gov (United States)

    Scarpellini, E; Boecxstaens, V; Farré, R; Bisschops, R; Dewulf, D; Gasbarrini, A; Pauwels, A; Blondeau, K; Tack, J

    2015-07-01

    Previous studies established that a pocket of highly acidic gastric juice is present postprandially at the gastroesophageal junction in man. The GABA-B agonist baclofen inhibits postprandial reflux events through its effects on the lower esophageal sphincter (LES). The aim of the current study was to investigate whether baclofen would affect the location and the extent of the postprandial acid pocket in healthy volunteers. Twelve healthy volunteers underwent acid pocket studies on two different occasions, at least 1 week apart. LES position was determined preprandially with pull-through manometry. Dual pH electrode and manometry probe stepwise pull-through (1 cm/minute, LES-10 to +5 cm) was performed at 30-minute intervals for 150 minutes, with administration of placebo or baclofen 40 mg after the first and ingestion of a liquid meal after the second pull-through. After placebo, a significant drop in intragastric gastric pH was present at the gastroesophageal junction after the meal, reflecting the acid pocket, and this was associated with a drop in LES pressure. Baclofen did not affect the presence of the acid pocket, but prevented the postprandial drop in LES pressure, and the extent of the acid pocket above the upper margin of the manometrically located LES was significantly decreased by baclofen (1.6 ± 0.7 vs. 0.3 ± 0.4 cm at 60 minutes, 2.2 ± 0.6 vs. 0.2 ± 0.6 at 90 minutes, and 1.5 ± 0.5 vs. 0.7 ± 0.7 cm at 120 minutes, all P Baclofen does not alter the intragastric acid pocket, but limits its extension into the distal esophagus, probably through an increase in postprandial LES pressure.

  1. Efficacy of High-Dose Baclofen for Alcohol Use Disorder and Comorbid Bulimia: A Case Report.

    Science.gov (United States)

    Weibel, Sébastien; Lalanne, Laurence; Riegert, Myriam; Bertschy, Gilles

    2015-01-01

    High-dose baclofen is a promising treatment for alcohol use disorder, with a specific action on craving. A more general action on craving in other addictive disorders has been suggested based on the hypothesis of a common neurobiological pathway in addictions. We report the case of a woman with both alcohol use disorder and bulimia nervosa. There was a positive response to high-dose baclofen on alcohol craving, but no response on food craving. The case illustrates that craving could be differentially responsive to anti-craving drugs.

  2. High doses of Baclofen as suicide attempt in patients with alcohol use disorders - A serious concern.

    Science.gov (United States)

    Holla, Bharath; Gowda, Guru S; Prabhu, Lokesh; Baby, Sojan; Viswanath, Biju; Chand, Prabhat; Murthy, Pratima

    2015-10-01

    Baclofen is increasingly being used as an off label anti-craving agent in alcohol use disorders in various parts of the world. The lack of proper recommendations regarding the dosage has important implications for safety in clinical management. In this context, we report two patients who were started with Baclofen as an anti-craving agent, and later developed serious complications following acute self inflicted overdose. We also highlight the important mechanisms of such complications and precautions that needs to be exerted while prescribing.

  3. GABAB Receptor Agonist R-Baclofen Reverses Social Deficits and Reduces Repetitive Behavior in Two Mouse Models of Autism.

    Science.gov (United States)

    Silverman, J L; Pride, M C; Hayes, J E; Puhger, K R; Butler-Struben, H M; Baker, S; Crawley, J N

    2015-08-01

    Autism spectrum disorder (ASD) is diagnosed by two core behavioral criteria, unusual reciprocal social interactions and communication, and stereotyped, repetitive behaviors with restricted interests. Excitatory/inhibitory imbalance is a prominent hypothesis for the etiology of autism. The selective GABAB receptor agonist R-baclofen previously reversed social deficits and reduced repetitive behaviors in a mouse model of Fragile X syndrome, and Arbaclofen improved some clinical symptoms in some Fragile X and ASD patients. To evaluate R-baclofen in a broader range of mouse models of ASD, we tested both the R-baclofen enantiomer and the less potent S-baclofen enantiomer in two inbred strains of mice that display low sociability and/or high repetitive or stereotyped behaviors. R-baclofen treatment reversed social approach deficits in BTBR T+ Itpr3tf/J (BTBR), reduced repetitive self-grooming and high marble burying scores in BTBR, and reduced stereotyped jumping in C58/J (C58), at nonsedating doses. S-baclofen produced minimal effects at the same doses. These findings encourage investigations of R-baclofen in other preclinical model systems. Additional clinical studies may be warranted to further evaluate the hypothesis that the GABAB receptor represents a promising pharmacological target for treating appropriately stratified subsets of individuals with ASD.

  4. Baclofen for maintenance treatment of opioid dependence: A randomized double-blind placebo-controlled clinical trial [ISRCTN32121581

    Directory of Open Access Journals (Sweden)

    Ahmadi-Abhari Seyed Ali

    2003-11-01

    Full Text Available Abstract Background Results of preclinical studies suggest that the GABAB receptor agonist baclofen may be useful in treatment of opioid dependence. This study was aimed at assessing the possible efficacy of baclofen for maintenance treatment of opioid dependence. Methods A total of 40 opioid-dependent patients were detoxified and randomly assigned to receive baclofen (60 mg/day or placebo in a 12-week, double blind, parallel-group trial. Primary outcome measure was retention in treatment. Secondary outcome measures included opioids and alcohol use according to urinalysis and self-report ratings, intensity of opioid craving assessed with a visual analogue scale, opioid withdrawal symptoms as measured by the Short Opiate Withdrawal Scale and depression scores on the Hamilton inventory. Results Treatment retention was significantly higher in the baclofen group. Baclofen also showed a significant superiority over placebo in terms of opiate withdrawal syndrome and depressive symptoms. Non-significant, but generally favorable responses were seen in the baclofen group with other outcome measures including intensity of opioid craving and self-reported opioid and alcohol use. However, no significant difference was seen in the rates of opioid-positive urine tests. Additionally, the drug side effects of the two groups were not significantly different. Conclusion The results support further study of baclofen in the maintenance treatment of opioid dependence.

  5. Effects of baclofen and naltrexone, alone and in combination, on the consumption of palatable food in male rats.

    Science.gov (United States)

    Avena, Nicole M; Bocarsly, Miriam E; Murray, Susan; Gold, Mark S

    2014-10-01

    Excess consumption of palatable food has been shown to affect reward-related brain regions, and pharmaceutical treatments for drug addiction may also be effective in treating overeating of such foods. The GABA-B agonist baclofen and opioid antagonist naltrexone have both been used to treat addiction, and have been shown to suppress intake of certain foods. The combination of these drugs has shown to be more effective in reducing alcohol consumption than either drug alone. The present study assessed the effects of naltrexone and baclofen, alone and in combination, on intake of foods comprised of various macronutrients. Male Sprague-Dawley rats were given 12-hr daily access to chow and a fat emulsion, sugar-fat emulsion, or a sugar solution for 21 days. Rats were then administered (intraperitoneal) baclofen-naltrexone combinations (0.1 mg/kg naltrexone and 1.0 mg/kg baclofen, 1.0 mg/kg naltrexone and 1.8 mg/kg baclofen), and naltrexone (0.1, 1.0 mg/kg) and baclofen (1.0, 1.8 mg/kg) alone. The high dose of the baclofen-naltrexone combination reduced palatable food intake in both the fat and sugar-fat groups compared with vehicle, without affecting chow consumption in these groups. Naltrexone showed little significant effects on intake of either palatable food or chow. Baclofen also reduced palatable food intake in the fat and fat-sugar groups, but differences were only noted between the low and high dose. The combination of baclofen and naltrexone may be a useful tool in selectively targeting the consumption of high-fat and sugar- and fat-rich foods.

  6. Positive experience with intrathecal baclofen treatment in children with severe cerebral palsy

    DEFF Research Database (Denmark)

    Overgård, Tinett Martesen; Kjærsgaard-Hansen, Lars; Søe, Morten;

    2015-01-01

    INTRODUCTION: Treatment of severe spasticity and dystonia with intrathecal baclofen (ITB) in children has been shown to be effective and has therefore been employed in the Region of Southern Denmark. The aim of this retrospective study was to analyse the efficacy and adverse events since ITB was ...

  7. Diazepam withdrawal responses measured in the social interaction test of anxiety and their reversal by baclofen.

    Science.gov (United States)

    File, S E; Mabbutt, P S; Andrews, N

    1991-01-01

    After 21 days of treatment with diazepam (0.5 or 2 mg/kg/day) rats were tolerant to the effects of diazepam to increase social interaction in the low light unfamiliar test condition of the social interaction test of anxiety. When they were tested 24 h after the last of 21 injections they showed significant decreases in social interaction, indicating an anxiogenic withdrawal response. However, the social interaction scores of rats tested 48 h after withdrawal from diazepam treatment were no longer different from those of the control group. The decreased social interaction, indicating increased anxiety, detected 24 h after withdrawal of diazepam (21 daily injections of 0.5 or 2 mg/kg), could be reversed by the usual daily diazepam dose (0.5 or 2 mg/kg, respectively) or by baclofen (0.5 or 1 mg/kg). Baclofen (2 mg/kg) was sedative in both control treated and diazepam-dependent rats, but was ineffective at reversing the decrease in social interaction seen after diazepam withdrawal. Possible sites of action mediating these effects of baclofen are discussed, and it is suggested that either post-synaptic GABAB sites in the hippocampus are involved or that the reversal of the decreased social interaction detected on withdrawal of diazepam treatment is due to a baclofen-mediated inhibition of 5-HT release in the hippocampus.

  8. Isobolographic analysis of interaction between vigabatrin and baclofen in the formalin test in mice.

    Science.gov (United States)

    Czuczwar, M; Kiś, J; Potasiński, A; Turski, W A; Przesmycki, K

    2001-01-01

    Vigabatrin and baclofen given together, at doses not affecting motor performance, produced dose-dependent inhibition of both phases in the formalin test in mice. Isobolographic analysis revealed a significant synergy between both drugs in both phases of the forrmalin test.

  9. Formulation and evaluation of gastroretentive microballoons containing baclofen for a floating oral controlled drug delivery system.

    Science.gov (United States)

    Dube, T S; Ranpise, N S; Ranade, A N

    2014-01-01

    The objective of the present study was to fabricate and evaluate a multiparticulate oral gastroretentive dosage form of baclofen characterized by a central large cavity (hollow core) promoting unmitigated floatation with practical applications to alleviate the signs and symptoms of spasticity and muscular rigidity. Solvent diffusion and evaporation procedure were applied to prepare floating microspheres with a central large cavity using various combinations of ethylcellulose (release retardant) and HPMC K4M (release modifier) dissolved in a mixture of dichloromethane and methanol (2:1). The obtained microspheres (700-1000 µm) exhibit excellent floating ability (86 ± 2.00%) and release characteristics with entrapment efficiency of 95.2 ± 0.32%. Microspheres fabricated with ethylcellulose to HPMC K4M in the ratio 8.5:1.5 released 98.67% of the entrapped drug in 12 h. Muscle relaxation caused by baclofen microspheres impairs the rotarod performance for more than 12 h. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate- labeled microspheres was no less than 10 h. The buoyant baclofen microspheres provide a promising gastroretentive drug delivery system to deliver baclofen in spastic patients with a sustained release rate.

  10. Baclofen as relapse prevention in the treatment of gamma-hydroxybutyrate dependence: a case series.

    Science.gov (United States)

    Kamal, Rama M; Loonen, Anton J M; Dijkstra, Boukje A G; De Jong, Cornelis A J

    2015-06-01

    In the last decade, gamma-hydroxybutyrate (GHB) abuse and dependence have increased. It has been reported that GHB dependence has a high rate of relapse, serious complications of intoxication, and a potentially life-threatening withdrawal syndrome. Nevertheless, in clinical practice, there is no known medical treatment to support GHB relapse prevention. We describe a case series of patients who were supported through an off-label treatment with baclofen to avoid a relapse into GHB abuse, for a period of 12 weeks. Nine of 11 patients did not relapse while taking a dose ranging from 30 to 60 mg per day, one patient relapsed after 5 weeks, and one stopped after 7 weeks. Baclofen was well tolerated; patients reported mild side effects such as fatigue, nausea, dry mouth, excessive sweating, and depressive feelings. Although systematic evidence is still lacking, our practice-based experience suggests that treatment with baclofen to assist abstinence might be effective in patients with GHB dependence. Further systematic controlled studies are necessary to establish the exact efficacy and safety of baclofen as relapse prevention for GHB-dependent patients.

  11. Baclofen reversed thermal place preference in rats with chronic constriction injury.

    Science.gov (United States)

    Salte, K; Lea, G; Franek, M; Vaculin, S

    2016-06-20

    Chronic constriction injury to the sciatic nerve was used as an animal model of neuropathic pain. Instead of frequently used reflex-based tests we used an operant thermal place preference test to evaluate signs of neuropathic pain and the effect of baclofen administration in rats with neuropathy. Chronic constriction injury was induced by four loose ligations of the sciatic nerve. Thermal place preference (45 °C vs. 22 °C and 45 °C vs. 11 °C) was measured after the ligation and after the administration of baclofen in sham and experimental rats. Rats with the chronic constriction injury spent significantly less time on the colder plate compared to sham operated animals at the combination 45 °C vs. 11 °C. After administration of baclofen (10 mg/kg s.c.), the aversion to the colder plate in rats with chronic constriction injury disappeared. At the combination 45 °C vs. 22 °C, no difference in time spent on colder and/or warmer plate was found between sham and experimental animals. These findings show the importance of cold allodynia evaluation in rats with chronic constriction injury and the effectiveness of baclofen in this neuropathic pain model.

  12. Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations.

    Science.gov (United States)

    Vlavonou, Raphaël; Perreault, Marc M; Barrière, Olivier; Shink, Eric; Tremblay, Pierre-Olivier; Larouche, Richard; Pichette, Vincent; Tanguay, Mario

    2014-05-01

    The pharmacokinetics of baclofen is well delineated in subjects with normal kidney function (KF); however, pharmacokinetics data in patients with chronic kidney disease (CKD) are not and dosage recommendations remain empirical. The effects of CKD on baclofen pharmacokinetics were assessed through a multi-center, open-label, single 5-mg dose, pharmacokinetics study. The KF was measured as the creatinine clearance (CrCL) calculated with the Cockroft-Gault (C-G) equation or as the estimated glomerular filtration rate (eGFR) using subjects' CKD-EPI equation. Subjects were assigned to 1 of 4 groups based on their CrCL (>80 mL/min, 50-80 mL/min; 30-50 mL/min and Baclofen's oral clearance and CrCL were statistically significantly correlated, and the trend was the same when classifying subjects either with the CKD-EPI or C-G equations. Linear equations using KF as variable were set to recommend individual dose reduction in CKD patients. Results suggest a mean dose reduction of 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD respectively, in order to achieve baclofen exposure comparable to that observed in healthy subjects.

  13. Clinical relevance of pharmacological and physiological data in intrathecal baclofen therapy

    NARCIS (Netherlands)

    Heetla, Herre W; Staal, Michael; Proost, Johannes H; van Laar, Teus

    2014-01-01

    Objective: To review all pharmacological and physiological data available on intrathecal baclofen (ITB) therapy and to evaluate its use in clinical practice and future research. Data Sources: PubMed was searched for relevant anatomic, physiological, and pharmacological data available on ITB. Study S

  14. Intrathecal baclofen pump, useful and safe therapeutic intervention in spasticity? Report of four cases

    Directory of Open Access Journals (Sweden)

    Cáceres-Jerez, Luz Elena

    2016-10-01

    Full Text Available Spasticity may cause immobility, prostration, chronic pain, bedsores, infections, thrombosis and pneumonia; the purposes of its treatment are to control pain, improve mobility and quality of life, and reincorporate the patient to its daily activities by means of oral anti-spastic drugs; however, patients suffering from severe spasticity may require high oral doses of these medications, which may lead to adverse effects. In such cases, intrathecal baclofen has been proposed as a solution. This procedure has not been widely used in Colombia, so that protocols to perform it have not been established. We report the results obtained with the intrathecal administration of baclofen in four severely spastic patients, who had not previously responded to oral anti-spastic drugs, including high doses of baclofen. Pain, spasticity and quality of life significantly improved in three of them. The remaining one presented tolerance to the medication. Intrathecal baclofen pump is a useful and safe procedure for patients with severe spasticity and poor response to oral treatment.

  15. Effects of baclofen and raclopride on reinstatement of cocaine self-administration in the rat.

    Science.gov (United States)

    Froger-Colléaux, Christelle; Castagné, Vincent

    2016-04-15

    At present there is no satisfactory treatment against relapse of drug-seeking behavior. Relapse can be modeled in laboratory animals using reinstatement procedures, whereby previously extinguished self-administration for a drug is reinstated by different factors, such as exposure to cues or drug priming. It is thought that activation of gamma-aminobutyric acid (GABA) B receptor complexes could represent a promising approach to pharmacotherapy for diminishing relapse potential with drugs possessing reinforcing properties. The effects of baclofen (a prototypic GABAB receptor agonist) on cue-induced cocaine reinstatement were evaluated in the rat with or without a priming injection of cocaine. The effects of raclopride (an antagonist of dopamine D2 receptors) were also evaluated. Cue-induced reinstatement under vehicle resulted in a significant increase in the number of presses on the active lever, as compared with extinction lever responding. This effect was accentuated in rats receiving a priming injection of cocaine (cocaine-plus-cue-induced reinstatement). Baclofen, at doses without effects on food-motivated operant behavior (2.5 and 5mg/kg i.p.), dose-dependently decreased the number of active lever presses during cue-induced reinstatement. Baclofen had slightly weaker effects on cocaine-plus-cue-induced reinstatement. Raclopride (0.08 and 0.15 mg/kg s.c.) had similar effects against cue-induced reinstatement although it failed to inhibit cocaine-plus-cue-induced reinstatement at the lower dose. Baclofen dose-dependently and selectively decreased reinstatement of cocaine self-administration. The data obtained provide support for the potential anti-craving efficacy of baclofen in the treatment of cocaine drug-seeking.

  16. Effect of the GABA B agonist baclofen on dipyrone-induced delayed gastric emptying in rats

    Directory of Open Access Journals (Sweden)

    E.F. Collares

    2005-01-01

    Full Text Available Dipyrone administered intravenously (iv or intracerebroventricularly (icv delays gastric emptying (GE in rats. Gamma-aminobutyric acid (GABA is the most potent inhibitory neurotransmitter of the central nervous system. The objective of the present study was to determine the effect of icv baclofen, a GABA B receptor agonist, on delayed GE induced by dipyrone. Adult male Wistar rats received a saline test meal containing phenol red as a marker. GE was indirectly evaluated by determining the percent of gastric retention (%GR of the meal 10 min after orogastric administration. In the first experiment, the animals were injected iv with vehicle (Civ or 80 mg/kg (240 µmol/kg dipyrone (Dp iv, followed by icv injection of 10 µl vehicle (bac0, or 0.5 (bac0.5, 1 (bac1 or 2 µg (bac2 baclofen. In the second experiment, the animals were injected icv with 5 µl vehicle (Cicv or an equal volume of a solution containing 4 µmol (1333.2 µg dipyrone (Dp icv, followed by 5 µl vehicle (bac0 or 1 µg baclofen (bac1. GE was determined 10 min after icv injection. There was no significant difference between control animals from one experiment to another concerning GR values. Baclofen at the doses of 1 and 2 µg significantly reduced mean %GR induced by iv dipyrone (Dp iv bac1 = 35.9% and Dp iv bac2 = 26.9% vs Dp iv bac0 = 51.8%. Similarly, baclofen significantly reduced the effect of dipyrone injected icv (mean %GR: Dp icv bac1 = 30.4% vs Dp icv bac0 = 54.2%. The present results suggest that dipyrone induces delayed GE through a route in the central nervous system that is blocked by the activation of GABA B receptors.

  17. Differential action of (-)-baclofen on the primary afferent depolarization produced by segmental and descending inputs.

    Science.gov (United States)

    Quevedo, J; Eguibar, J R; Jiménez, I; Rudomin, P

    1992-01-01

    The purpose of the present series of experiments was to analyze, in anesthetized and paralyzed cats, the effects of (-)-baclofen and picrotoxin on the primary afferent depolarization (PAD) generated in single Ib afferent fibers by either intraspinal microstimulation or stimulation of the segmental and descending pathways. PAD was estimated by recording dorsal root potentials and by measuring the changes in the intraspinal activation threshold of single Ib muscle afferent fibers. The PAD elicited by stimulation of group I muscle or cutaneous afferents was readily depressed and often abolished 20-40 min after the intravenous injection of 1-2 mg/kg (-)-baclofen. In contrast, the same amounts of (-)-baclofen produced a relatively small depression of the PAD elicited by stimulation of the brainstem reticular formation (RF). The monosynaptic PAD produced in single Ib fibers by intraspinal microstimulation within the intermediate nucleus was depressed and sometimes abolished following the i.v. injections of 1-2 mg/kg (-)-baclofen. Twenty to forty minutes after the i.v. injection of picrotoxin (0.5-1 mg/kg), there was a strong depression of the PAD elicited by stimulation of muscle and cutaneous afferents as well as of the PAD produced by stimulation of the RF and the PAD produced by intraspinal microstimulation. The results obtained suggest that, in addition to its action on primary afferents, (-)-baclofen may depress impulse activity and/or transmitter release in a population of last-order GABAergic interneurons that mediate the PAD of Ib fibers. The existence of GABAb autoreceptors in last-order interneurons mediating the PAD may function as a self-limiting mechanism controlling the synaptic efficacy of these interneurons.

  18. Ga Ba{sub B} pharmacophoric pattern based on conformational analysis of 3-hetero aromatic baclofen analogues

    Energy Technology Data Exchange (ETDEWEB)

    Pirard, B.; Paquet, B.; Evrard, G.; Durant, F. [Facultes Universitaires Notre-Dame de la Paix, Namur (Belgium); Berthelot, P.; Vaccher, C.; Ansard, M.H.; Debaert, M. [UFR de Pharmacie, 59 - Lille (France)

    1995-12-31

    Substituting a furan, a thiophen, a benzo (b) furan or a benzo (b) thiophen ring for the p-chlorophenyl moiety of baclofen has led to GABA{sub B} (GABA = {gamma}-aminobutyric acid) ligands with different affinities according to the nature of the hetero-aromatic ring, and the nature and position of its substituent. In order to determine the structural requirements that are important for GABA{sub B} affinity, we have aligned the 3D structures of several 3-hetero-aromatic baclofen analogues with that of baclofen. As a result, we have suggested a pharmacophoric pattern for 3-hetero-aromatic baclofen analogues. The 3D structures have been studied by X-ray diffraction and by ab initio molecular orbital calculations. (authors). 29 refs., 6 figs., 5 tabs.

  19. High-dose baclofen for the treatment of alcohol dependence (BACLAD study): a randomized, placebo-controlled trial.

    Science.gov (United States)

    Müller, Christian A; Geisel, Olga; Pelz, Patricia; Higl, Verena; Krüger, Josephine; Stickel, Anna; Beck, Anne; Wernecke, Klaus-Dieter; Hellweg, Rainer; Heinz, Andreas

    2015-08-01

    Previous randomized, placebo-controlled trials (RCTs) assessing the efficacy of the selective γ-aminobutyric acid (GABA)-B receptor agonist baclofen in the treatment of alcohol dependence have reported divergent results, possibly related to the low to medium dosages of baclofen used in these studies (30-80mg/d). Based on preclinical observations of a dose-dependent effect and positive case reports in alcohol-dependent patients, the present RCT aimed to assess the efficacy and safety of individually titrated high-dose baclofen for the treatment of alcohol dependence. Out of 93 alcohol-dependent patients initially screened, 56 were randomly assigned to a double-blind treatment with individually titrated baclofen or placebo using dosages of 30-270mg/d. The multiple primary outcome measures were (1) total abstinence and (2) cumulative abstinence duration during a 12-week high-dose phase. More patients of the baclofen group maintained total abstinence during the high-dose phase than those receiving placebo (15/22, 68.2% vs. 5/21, 23.8%, p=0.014). Cumulative abstinence duration was significantly higher in patients given baclofen compared to patients of the placebo group (mean 67.8 (SD 30) vs. 51.8 (SD 29.6) days, p=0.047). No drug-related serious adverse events were observed during the trial. Individually titrated high-dose baclofen effectively supported alcohol-dependent patients in maintaining alcohol abstinence and showed a high tolerability, even in the event of relapse. These results provide further evidence for the potential of baclofen, thereby possibly extending the current pharmacological treatment options in alcohol dependence.

  20. The Effects of Baclofen for the Treatment of Gastroesophageal Reflux Disease: A Meta-Analysis of Randomized Controlled Trials

    Directory of Open Access Journals (Sweden)

    Shujie Li

    2014-01-01

    Full Text Available Objectives. Baclofen can relieve gastroesophageal reflux-related symptoms in healthy subjects and gastroesophageal reflux disease (GERD patients by reducing the incidence of transient lower esophageal sphincter relaxation. This meta-analysis aimed to evaluate the efficacy and safety of baclofen for the treatment of GERD. Methods. We systematically searched randomized controlled trials published prior to November 2013 from PubMed, Medline, Embase, ScienceDirect, ClinicalTrials.gov, and the Cochrane Central Register of Randomized Controlled Trials. We performed a meta-analysis of all eligible trials. Results. Nine studies were identified with a total of 283 GERD patients and healthy subjects. Comparative analysis provided high quality data supporting the ability of baclofen to promote a short-term decrease in the number of reflux episodes per patient, the average length of reflux episodes, and the incidence of transient lower esophageal sphincter relaxation. No serious adverse events or death events were reported, and there were no significant differences in the overall adverse events between baclofen and placebo. All reported side effects of baclofen were of mild-to-moderate intensity, and the drug was well tolerated. Conclusion. Abundant evidence suggests that baclofen may be a useful approach for the treatment of GERD patients; however, a larger well-designed research study would further confirm this recommendation.

  1. Baclofen novel gastroretentive extended release gellan gum superporous hydrogel hybrid system: in vitro and in vivo evaluation.

    Science.gov (United States)

    El-Said, Ibrahim A; Aboelwafa, Ahmed A; Khalil, Rawia M; ElGazayerly, Omaima N

    2016-01-01

    Baclofen is a centrally acting skeletal muscle relaxant with a short elimination half-life, which results in frequent daily dosing and subsequent poor patient compliance. The narrow absorption window of baclofen in the upper gastrointestinal tract limits its formulation as extended release dosage forms. In this study, baclofen extended release superporous hydrogel (SPH) systems, including conventional SPH, SPH composite and SPH hybrid (SPHH), were prepared aiming to increase the residence of baclofen at its absorption window. The applicability of different polymers, namely, gellan gum, guar gum, polyvinyl alcohol and gelatin, was investigated in preparation of SPHH systems. The prepared SPH systems were evaluated regarding weight and volume swelling ratio, porosity, mechanical properties, incorporation efficiency, degree of erosion and drug release. In vivo assessment was performed in dogs to evaluate gastric residence time by X-ray studies. In addition, the oral bioavailability of baclofen relative to commercially available Lioresal® immediate release tablets was also investigated. The novel baclofen gellan SPHH cross linked with calcium chloride was characterized by optimum mechanical properties, acceptable swelling properties as well as extended drug release. It also exhibited a prolonged plasma profile when compared to twice daily administered Lioresal®.

  2. Serum levels of brain-derived neurotrophic factor in alcohol-dependent patients receiving high-dose baclofen.

    Science.gov (United States)

    Geisel, Olga; Hellweg, Rainer; Müller, Christian A

    2016-06-30

    The neurotrophin brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the development and maintenance of addictive and other psychiatric disorders. Also, interactions of γ-aminobutyric acid (GABA)-ergic compounds and BDNF have been reported. The objective of this study was to investigate serum levels of BDNF over time in alcohol-dependent patients receiving individually titrated high-dose treatment (30-270mg/d) with the GABA-B receptor agonist baclofen or placebo for up to 20 weeks. Serum levels of BDNF were measured in patients of the baclofen/placebo group at baseline (t0), 2 weeks after reaching individual high-dose of baclofen/placebo treatment (t1) and after termination of study medication (t2) in comparison to carefully matched healthy controls. No significant differences in serum levels of BDNF between the baclofen and the placebo group or healthy controls were found at t0, t1, or at t2. Based on these findings, it seems unlikely that baclofen exerts a direct effect on serum levels of BDNF in alcohol-dependent patients. Future studies are needed to further explore the mechanism of action of baclofen and its possible relationship to BDNF in alcohol use disorders.

  3. The synthesis and biodistribution of 3-(4'-[[sup 125]I]-iodophenyl)-4-aminobutyric acid, a radioiodinated analogue of baclofen

    Energy Technology Data Exchange (ETDEWEB)

    Wakita, Y.; Kojima, M. (Kyushu Univ., Fukuoka (Japan). Div. of Radiopharmaceutical Chemistry); Schwendner, S.W.; McConnell, D.; Counsell, R.E. (Michigan Univ., Ann Arbor, MI (United States). School of Medicine)

    1990-02-01

    Baclofen has been found to bind to receptors in the central nervous system that are specific for [gamma]-aminobutyric acid (GABA), a well known inhibitory neurotransmitter. This paper describes the synthesis of a radioiodinated analog of baclofen as part of an effort to develop receptor probes useful in single photon emission computed tomography. Preliminary biodistribution studies showed the radioiodinationed analog to be essentially stable to in vivo deiodination and have a distribution profile similar to that of baclofen. (Author).

  4. Prospective Randomized Study of Oral Diazepam and Baclofen on Spasticity in Cerebral Palsy

    Science.gov (United States)

    Laisram, Nonica; Wadhwa, Ranjan Kumar; Kothari, Shashank Yashwant

    2016-01-01

    Introduction Spastic cerebral palsy (CP) is the most common form of CP. Diazepam and Baclofen are the most commonly used oral drugs to manage spasticity. Study was designed to evaluate and compare their effects and safety in CP children. Aim Study was aimed to assess and compare outcome of oral Diazepam and Baclofen in spastic cerebral palsy children in terms of extent of reduction of spasticity and side effects profile. Materials and Methods Randomized prospective follow-up study was done for one year after giving Diazepam and Baclofen in weekly incremental doses upto recommended maximum dose to 60 children for three months. Two primary outcome measures were spasticity reduction and adverse effect profile. Spasticity reduction was measured by Modified Ashworth’s Scale (MAS) and Range of Motion improvement (ROM). Results After random allocation, there was no baseline difference between groups. Mean MAS score improved from 1.96±0.4 at baseline to 1.63±0.40 and 1.41± 0.36 at 1 month and 3 months for Diazepam and from 1.84±0.64 to 1.57±0.59 and 1.31± 0.48 respectively for Baclofen. Within the group reduction was significant with p-value = 0.0001. Intergroup comparison showed no statistically significant difference with p-value of 0.48 and 0.22 at 1 and 3 months. Baseline ROM showed significant improvement at 1 and 3 months with p value of 0.004 and 0.001 for Diazepam and 0.01 and 0.000 for Baclofen respectively with no statistically significant difference among two groups. Drowsiness was most common observed side effect in both the groups. Conclusion Patients showed significant improvement in spasticity as measured by Mean MAS score and range of motion in Diazepam as well as Baclofen group. Both drugs were found safe for use in children. Study couldn’t establish any difference between the two drugs. However studies with bigger sample size and longer follow- up assessing functional improvement in patients will be required in near future. PMID:27504360

  5. Intrathecal baclofen therapy for spasticity of cerebral origin: cerebral palsy and brain injury.

    Science.gov (United States)

    Nuttin, B; Ivanhoe, C; Albright, L; Dimitrijevic, M; Saltuari, L

    1999-04-01

    Spasticity affects approximately 66% of individuals with cerebral palsy and 14% of the 100,000 individuals who, each year, experience brain injury in the US. This spasticity interferes with motor function and limits range of motion. It may cause pain and impede mobility, transfers, activities of daily living, sitting posture, and sleep. In addition, spasticity can contribute to the formation of pressure sores and joint contractures and make nursing or caregiving difficult. Several treatment options are available for intractable spasticity. For some diagnoses, oral medications are still the treatment of choice, while in other settings injection therapy may be more appropriate. If, however, they are ineffective or cause too many side effects, intrathecal baclofen therapy (ITB) may be a valuable alternative. ITB is effective, nondestructive, titratable, and reversible. In addition, it is associated with fewer CNS-related side effects than oral Lioresal (Novartis Pharma AG, Basel, Switzerland). Intrathecal baclofen therapy may improve range of motion, facilitate movement, reduce the patient's expenditure of energy, facilitate nursing, reduce the risk of developing contractures, and, in some cases, diminish pain resulting from spasticity and/or spasms. It also may improve speech, gait, upper extremity function, and activities of daily living, including communication, eating, dressing, hygiene, and other aspects of self-care. A recent study shows that treatment with intrathecal baclofen reduces the need for corrective orthopedic surgeries. Patient selection should be done in a multidisciplinary spasticity setting, where the expertise for different treatment modalities is available. Patients must be screened for response to the drug prior to implantation of the drug delivery pump. Maintenance doses for intrathecal baclofen range from 22 to 1400 μg/day, with most patients adequately maintained on 90-703 μg/day. Complications, while rare, are most often related to the

  6. Intrathecal baclofen withdrawal resembling serotonin syndrome in an adolescent boy with cerebral palsy.

    Science.gov (United States)

    Salazar, Maria L; Eiland, Lea S

    2008-10-01

    Intrathecal baclofen (ITB) is increasingly being used to reduce spasticity among children with cerebral palsy, dystonia, and spinal cord injuries. However, complications such as withdrawal, which is a potentially life-threatening condition, can occur. Intrathecal baclofen withdrawal should be differentiated with autonomic dysreflexia, malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. We report a case of ITB withdrawal secondary to low residual volume in the pump reservoir and resembling serotonin syndrome in an adolescent with cerebral palsy. He presented with agitation, diaphoresis, increasing spasticity, rigidity, jitteriness, hyperreflexia, clonus, tachycardia, hypertension, and rhabdomyolysis. Treatment consisted of emergent refilling of the pump, intravenous diazepam, and oral cyproheptadine. We also emphasize the importance of prompt recognition of ITB withdrawal among high-risk patients.

  7. Baclofen influences lipopolysaccharide-mediated interleukin-6 release from murine pituicytes

    DEFF Research Database (Denmark)

    Kjeldsen, Tine H; Hansen, Erik W; Christensen, Jens D

    2002-01-01

    -6 release from pituicytes. Cultured murine pituicytes were stimulated for 24 h with lipopolysaccharide (0.5 ng/ml) to give a significant interleukin-6 release compared to control. The interleukin-6 release was significantly potentiated by the GABA(B) receptor agonist (R)-4-amino-3-(4-chlorophenyl......Pituicytes, the glial cells of the neurohypophysis, secrete interleukin-6 upon stimulation with various inflammatory mediators, i.e. lipopolysaccharide. Previous studies have identified several receptors on pituicytes. This study investigates the effect of GABA(B) receptor activation on interleukin......) butanoic acid (R-baclofen; 10, 100 or 500 microM). However, R-baclofen itself (10, 100 or 500 microM) did not stimulate the interleukin-6 secretion. Furthermore, the potent GABA(B) receptor antagonists 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl]diethoxymethyl) phosphinic acid (CGP52432; 30 or 300 micro...

  8. Detection of compatibility between baclofen and excipients with aid of infrared spectroscopy and chemometry

    Science.gov (United States)

    Rojek, Barbara; Wesolowski, Marek; Suchacz, Bogdan

    2013-12-01

    In the paper infrared (IR) spectroscopy and multivariate exploration techniques: principal component analysis (PCA) and cluster analysis (CA) were applied as supportive methods for the detection of physicochemical incompatibilities between baclofen and excipients. In the course of research, the most useful rotational strategy in PCA proved to be varimax normalized, while in CA Ward's hierarchical agglomeration with Euclidean distance measure enabled to yield the most interpretable results. Chemometrical calculations confirmed the suitability of PCA and CA as the auxiliary methods for interpretation of infrared spectra in order to recognize whether compatibilities or incompatibilities between active substance and excipients occur. On the basis of IR spectra and the results of PCA and CA it was possible to demonstrate that the presence of lactose, β-cyclodextrin and meglumine in binary mixtures produce interactions with baclofen. The results were verified using differential scanning calorimetry, differential thermal analysis, thermogravimetry/differential thermogravimetry and X-ray powder diffraction analyses.

  9. Indwelling intrathecal catheter with subcutaneous abdominal reservoir: a viable baclofen delivery system in severely cachectic patients.

    Science.gov (United States)

    Waqar, Mueez; Ellenbogen, Jonathan R; Kumar, Ram; Sneade, Christine; Zebian, Bassel; Williams, Dawn; Pettorini, Benedetta L

    2014-10-01

    Intrathecal baclofen (ITB) is a reversible treatment that reduces muscle tone to ameliorate spasticity and dystonia in patients with cerebral palsy (CP). The resulting decrease in energy expenditure allows patients to gain much-needed weight, albeit temporarily. Modern techniques require sufficient abdominal musculature and subcutaneous fat to permit the implantation of an indwelling pump. In patients with extremely low muscle bulk, visceral pumps may be impractical or impossible, with increased risks of dehiscence and infection. The authors describe a variation of the classical procedure in a young patient with severe cachexia. A 10-year-old boy with spastic-dystonic quadriplegic CP was admitted to the neuromedical unit. Numerous drug trials had failed, and surgical intervention was deemed necessary but was complicated by his cachectic body habitus. The authors inserted a lumbar intrathecal catheter and subcutaneously tunneled it to the anterolateral abdomen, where it was connected to a subcutaneous injection port. Baclofen was continuously infused into the subcutaneous port using a noncoring needle connected to an external pump. The needle and line were changed every 5 days to minimize the risk of sepsis. Although other techniques, such as intraventricular baclofen delivery, have been described, these are largely dependent upon sufficient musculature to support a visceral pump. A subcutaneous injection port system represents an alternative approach that reduces the risk of sepsis and may be better tolerated in cachectic patients.

  10. Baclofen Protects Primary Rat Retinal Ganglion Cells from Chemical Hypoxia-Induced Apoptosis through the Akt and PERK Pathways

    Directory of Open Access Journals (Sweden)

    Pingping Fu

    2016-11-01

    Full Text Available Retinal ganglion cells (RGCs consume large quantities of energy to convert light information into a neuronal signal, which makes them highly susceptible to hypoxic injury. This study aimed to investigate the potential protection by baclofen, a GABAB receptor agonist, of retinal ganglion cells against hypoxia-induced apoptosis. CoCl2 was applied to mimic hypoxia. Primary rat retinal ganglion cells (RGCs were subjected to CoCl2 with or without baclofen treatment, and RNA interference techniques were used to knock down the GABAB2 gene in the primary RGCs. The viability and apoptosis of RGCs were assessed using cell viability and TUNEL assays, Hoechst staining, and flow cytometry. The expression of cleaved caspase-3, bcl-2, bax, Akt, phospho-Akt, PERK, phospho-PERK, eIF2α, phospho-eIF2α, ATF-4, and CHOP were measured using western blotting. GABAB2 mRNA expression was determined using quantitative real-time polymerase chain reaction (qRT-PCR analysis. Our study revealed that CoCl2 significantly induced RGC apoptosis and that baclofen reversed these effects. CoCl2-induced reduction of Akt activity was also reversed by baclofen. Baclofen prevented the activation of the PERK pathway and the increase in CHOP expression induced by CoCl2. Knockdown of GABAB2 and the inactivation of the Akt pathway by inhibitors reduced the protective effect of baclofen on CoCl2-treated RGCs. Taken together, these results demonstrate that baclofen protects RGCs from CoCl2-induced apoptosis by increasing Akt activity and by suppressing the PERK pathway and CHOP activation.

  11. Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial.

    Science.gov (United States)

    Beraha, Esther M; Salemink, Elske; Goudriaan, Anna E; Bakker, Abraham; de Jong, David; Smits, Natasha; Zwart, Jan Willem; Geest, Dick van; Bodewits, Pieter; Schiphof, Tom; Defourny, Harma; van Tricht, Mirjam; van den Brink, Wim; Wiers, Reinout W

    2016-12-01

    Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30-60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ(2)=0.41; p=0.813) or the 16-weeks complete medication period (χ(2)=0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered.

  12. Baclofen vs. Dextromethorphan in the treatment of coughing: a randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Shahriar M

    2010-01-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Cough is one of the most common symptoms for which outpatient care is sought. Since, a few research evaluated efficacy and therapeutic effect of baclofen in remedy of cough (especially chronic cough, In this study we compared the efficacy of oral Baclofen 20 mg with Dextromethorphan to improvement of cough in two groups."n"nMethods: In this double blind randomized clinical trial, 120 patients with chronic cough (up to three weeks that were referred to respiratory diseases clinic of Ali Ebn-e Abitaleb (AS hospital in Zahedan, Iran at 2007 were randomly devided to two groups. 60 peoples in each, (baclofen recipient group with mean age 32.32±6.51 and dextromethorphan recipient group with mean age 31.54±5.06 year were evaluated for qualitative decline of severity, period and duration of cough for 14 days. "n"nResults: In baclofen recipient group 73.3% and in dextromethorphan recipient group 65% all patients had decline of severity, period and duration of the cough. Statistically, there were no significant differences between two groups in regard to qualitative decline of severity, period and duration of cough (p>0.05. Also, there were no drug related side effects in the patients."n"nConclusions: Baclofen

  13. Effects of the GABA(B) receptor agonist baclofen administered orally on normal food intake and intraperitoneally on fat intake in non-deprived rats.

    Science.gov (United States)

    Bains, Rasneer S; Ebenezer, Ivor S

    2013-01-01

    It has been previously reported that the GABA(B) receptor agonist baclofen decreases food intake after oral administration and fat intake after intraperitoneal administration. The aim of the study was to investigate the effects of baclofen (1-4 mg/ kg) administered orally (Experiment 1) on food intake in non-deprived rats (n=6) and intraperitoneally (Experiment 2) on fat intake in non-deprived rats (n=8) that were naïve to baclofen (1st set of trials) and in the same group of rats after they were sub-chronically exposed to baclofen (2nd set of trials). The results from Experiment 1 show that baclofen had no effects on food intake during the 1st set of trials, but the 2 and 4 mg/kg doses significantly increased food consumption during the 2nd set of trials. Baclofen produced sedation during the 1st set of trials, but tolerance occurred to this effect and was not apparent during the 2nd set of trials. These observations suggest that the motor effects may have competed with the hyperphagic effects of baclofen during the 1st set of trials. The data from Experiment 2 show that baclofen had no effects on fat intake during either the 1st or 2nd set of trials. The results of the study thus indicate that orally administrated baclofen increases food intake and intraperitoneal administration has no effect on fat intake in non-deprived rats under the conditions used in this study. These findings may have important implications for research on the use of baclofen in studies concerned with ingestive behaviours.

  14. An isobolographic analysis of drug interaction between intrathecal clonidine and baclofen in the formalin test in rats.

    Science.gov (United States)

    Przesmycki, K; Dzieciuch, J A; Czuczwar, S J; Kleinrok, Z

    1998-01-01

    The inhibition of both phases of the formalin response by intrathecal (IT) clonidine and baclofen, given alone or in combination at a fixed dose ratio, was studied. Both drugs, at doses not affecting motor performance, produced a dose-dependent inhibition of phase 2 of the formalin test. The potency of baclofen and clonidine, defined by their ID50's for phase 2 of the formalin test, was 0.56 and 3.4 nmol, respectively. The combination ID50 of baclofen and clonidine, with the equieffective dose ratio of 1:6, was found to be statistically lower than the theoretical additive ID50. These data suggest that co-administration of alpha2-adrenoceptor or GABA(B) receptor agonists may prove therapeutically useful in treating chronic pain.

  15. Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

    Science.gov (United States)

    Pedrón, Valeria T; Varani, André P; Balerio, Graciela N

    2016-05-01

    In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and μ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression.

  16. Positive experience with intrathecal baclofen treatment in children with severe cerebral palsy

    DEFF Research Database (Denmark)

    Overgård, Tinett Martesen; Kjærsgaard-Hansen, Lars; Søe, Morten

    2015-01-01

    stated that ITB had been worthwhile, and 90.3% would recommend it to other parents. Most infectious and mechanical adverse events were experienced during the first 200 days after pump implantation. The total complication rate was 0.40 per pump year. CONCLUSION: ITB resulted in reduced spasticity...... was introduced in 2003. METHODS: A total of 46 children who had a baclofen pump from April 2003 to January 2013 were included. The children's medical records were reviewed and clinical characteristics, efficacy and adverse events were registered. The efficacy of treatment experienced by parents was ascertained...

  17. Baclofen in the Therapeutic of Sequele of Traumatic Brain Injury: Spasticity.

    Science.gov (United States)

    Pérez-Arredondo, Adán; Cázares-Ramírez, Eduardo; Carrillo-Mora, Paul; Martínez-Vargas, Marina; Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Alemón-Medina, Radamés; Sampieri, Aristides; Navarro, Luz; Carmona-Aparicio, Liliana

    Traumatic brain injury (TBI) is an alteration in brain function, caused by an external force, which may be a hit on the skull, rapid acceleration or deceleration, penetration of an object, or shock waves from an explosion. Traumatic brain injury is a major cause of morbidity and mortality worldwide, with a high prevalence rate in pediatric patients, in which treatment options are still limited, not available at present neuroprotective drugs. Although the therapeutic management of these patients is varied and dependent on the severity of the injury, general techniques of drug types are handled, as well as physical and surgical. Baclofen is a muscle relaxant used to treat spasticity and improve mobility in patients with spinal cord injuries, relieving pain and muscle stiffness. Pharmacological support with baclofen is contradictory, because disruption of its oral administration may cause increased muscle tone syndrome and muscle spasm, prolonged seizures, hyperthermia, dysesthesia, hallucinations, or even multisystem organ failure. Combined treatments must consider the pathophysiology of broader alterations than only excitation/inhibition context, allowing the patient's reintegration with the greatest functionality.

  18. Does the Presence of a Hiatal Hernia Affect the Efficacy of the Reflux Inhibitor Baclofen During Add-On Therapy?

    NARCIS (Netherlands)

    H. Beaumont; G.E.E. Boeckxstaens

    2009-01-01

    OBJECTIVES: Reflux inhibitors, like the gamma-aminobutyric acid type B (GABA(B)) receptor agonist, baclofen, block transient lower esophageal sphincter relaxations (TLESRs) and are proposed as an add-on therapy in patients with proton pump inhibitor (PPI)-resistant gastroesophageal reflux. However,

  19. Intra-accumbens baclofen, but not muscimol, increases second order instrumental responding for food reward in rats.

    Directory of Open Access Journals (Sweden)

    Kim G T Pulman

    Full Text Available Stimulation of either GABA(A or GABA(B receptors within the nucleus accumbens shell strongly enhances food intake in rats. However the effects of subtype-selective stimulation of GABA receptors on instrumental responses for food reward are less well characterized. Here we contrast the effects of the GABA(A receptor agonist muscimol and GABA(B receptor agonist baclofen on instrumental responding for food using a second order reinforcement schedule. Bilateral intra-accumbens administration of baclofen (220-440 pmol stimulated responding but a higher dose (660 pmol induced stereotyped oral behaviour that interfered with responding. Baclofen (220-660 pmol also stimulated intake of freely available chow. Muscimol (220-660 pmol was without effect on responding for food on this schedule but did stimulate intake of freely available chow. Unilateral administration of either baclofen or muscimol (220 pmol induced similar patterns of c-fos immunoreactivity in several hypothalamic sites but differed in its induction in the central nucleus of the amygdala. We conclude that stimulation of GABA(A or GABA(B receptors in the nucleus accumbens shell of rats produces clearly distinguishable effects on operant responding for food.

  20. Controlled Study of the Effects of Continuous Intrathecal Baclofen Infusion in Non-Ambulant Children with Cerebral Palsy

    Science.gov (United States)

    Morton, Richard E.; Gray, Natalie; Vloeberghs, Michael

    2011-01-01

    Aim: To measure changes in children with severe spastic cerebral palsy (CP) after continuous intrathecal baclofen (ITB) infusion over 18 months and to compare the results with those of a comparison group awaiting treatment. Method: Thirty-eight children with severe spastic CP considered suitable for ITB were assessed when first seen, just before…

  1. Intrathecal Baclofen in Children with Spastic Cerebral Palsy: A Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Study

    Science.gov (United States)

    Hoving, Marjanke A.; van Raak, Elisabeth P. M.; Spincemaille, Geert H. J. J.; Palmans, Liesbeth J.; Sleypen, Frans A. M.; Vles, Johan S. H.

    2007-01-01

    Intrathecal baclofen (ITB) therapy can be very effective in the treatment of intractable spasticity, but its effectiveness and safety have not yet been thoroughly studied in children with cerebral palsy (CP). The aims of this double-blind, randomized, placebo-controlled, dose-finding study were to select children eligible for continuous ITB…

  2. Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.

    Directory of Open Access Journals (Sweden)

    Shunying Jin

    Full Text Available Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC deposition-induced acute lung injury (ALI. Components of gamma amino butyric acid (GABA signaling, including GABA B receptor 2 (GABABR2, GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP, in the bronchoalveolar lavage fluid (BALF. Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting

  3. Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.

    Science.gov (United States)

    Jin, Shunying; Merchant, Michael L; Ritzenthaler, Jeffrey D; McLeish, Kenneth R; Lederer, Eleanor D; Torres-Gonzalez, Edilson; Fraig, Mostafa; Barati, Michelle T; Lentsch, Alex B; Roman, Jesse; Klein, Jon B; Rane, Madhavi J

    2015-01-01

    Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP), in the bronchoalveolar lavage fluid (BALF). Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting a

  4. Chronic baclofen desensitizes GABA(B)-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain.

    Science.gov (United States)

    Keegan, Bradley M T; Beveridge, Thomas J R; Pezor, Jeffrey J; Xiao, Ruoyu; Sexton, Tammy; Childers, Steven R; Howlett, Allyn C

    2015-08-01

    The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-β (pGSK3β(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAK(Tyr397) and pGSK3β(Tyr216) compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32(Thr34)) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA

  5. Improvements in children with cerebral palsy following intrathecal baclofen: use of the Rehabilitation Institute of Chicago Care and Comfort Caregiver Questionnaire (RIC CareQ).

    Science.gov (United States)

    Baker, Karin W; Tann, Beverley; Mutlu, Akmer; Gaebler-Spira, Deborah

    2014-03-01

    Implantation of an intrathecal baclofen pump is recommended for children with cerebral palsy as a means to improve care and comfort when other options fail to control severe hypertonia. Making an assessment of a child's spasticity-related limitations in both routine care and activity is a necessary component of selection of intrathecal baclofen candidates. The Rehabilitation Institute of Chicago Care and Comfort Caregiver Questionnaire (RIC CareQ) is a validated, easy-to-use questionnaire that elicits information about the ease of daily activity and caregiving in patients with severe spasticity. Questionnaires completed by caregivers and patients at a pediatric physiatry spasticity clinic over an 11-year period were reviewed to evaluate whether the Rehabilitation Institute of Chicago Care and Comfort Caregiver Questionnaire captured improved caregiving and comfort of children with cerebral palsy and severe spasticity following intrathecal baclofen pump implantation. The Questionnaire scores showed improvement after intrathecal baclofen pump implantation, consistent with subjective reports of patient and caregiver satisfaction.

  6. Comparison of Efficacy and Side Effects of Oral Baclofen Versus Tizanidine Therapy with Adjuvant Botulinum Toxin Type A in Children With Cerebral Palsy and Spastic Equinus Foot Deformity.

    Science.gov (United States)

    Dai, Alper I; Aksoy, Sefika N; Demiryürek, Abdullah T

    2016-02-01

    This retrospective study aimed to compare the therapeutic response, including side effects, for oral baclofen versus oral tizanidine therapy with adjuvant botulinum toxin type A in a group of 64 pediatric patients diagnosed with static encephalopathy and spastic equinus foot deformity. Following botulinum toxin A treatment, clinical improvement led to the gradual reduction of baclofen or tizanidine dosing to one-third of the former dose. Gross Motor Functional Measure and Caregiver Health Questionnaire scores were markedly elevated post-botulinum toxin A treatment, with scores for the tizanidine (Gross Motor Functional Measure: 74.45 ± 3.72; Caregiver Health Questionnaire: 72.43 ± 4.29) group significantly higher than for the baclofen group (Gross Motor Functional Measure: 68.23 ± 2.66; Caregiver Health Questionnaire: 67.53 ± 2.67, P baclofen with adjuvant botulinum toxin A.

  7. Effects of the GABAB receptor-positive modulators CGP7930 and rac-BHFF in baclofen- and γ-hydroxybutyrate-discriminating pigeons.

    Science.gov (United States)

    Koek, Wouter; France, Charles P; Cheng, Kejun; Rice, Kenner C

    2012-05-01

    In vivo effects of GABA(B) receptor-positive modulators suggest them to have therapeutic potential to treat central nervous system disorders such as anxiety and drug abuse. Although these effects are thought to be mediated by positive modulation of GABA(B) receptors, such modulation has been examined primarily in vitro. This study further examined the in vivo properties of the GABA(B) receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). In pigeons discriminating baclofen from saline, γ-hydroxybutyrate (GHB) produced 100% baclofen-appropriate responding, and the GABA(B) antagonist 3-aminopropyl(dimethoxymethyl) phosphinic acid (CGP35348) blocked the effects of both drugs. CGP7930 and rac-BHFF produced at most 41 and 74% baclofen-appropriate responding, respectively, and enhanced the discriminative stimulus effects of baclofen, but not of GHB. In pigeons discriminating GHB from saline, CGP7930 and rac-BHFF produced at most 1 and 49% GHB-appropriate responding, respectively, and enhanced the effects of baclofen, but not of GHB. Enhancement of the discriminative stimulus effects of baclofen by rac-BHFF and CGP7930 is further evidence of their effectiveness as GABA(B) receptor-positive modulators in vivo. Furthermore, lack of complete substitution of the positive modulators rac-BHFF and CGP7930 for baclofen and GHB suggests that their discriminative stimulus effects differ from those of GABA(B) receptor agonists. Finally, together with converging evidence that the GABA(B) receptor populations mediating the effects of baclofen and GHB are not identical, the present findings suggest that these populations differ in their susceptibility to positive modulatory effects. Such differences could allow for more selective therapeutic targeting of the GABA(B) system.

  8. Intrathecal baclofen, a GABAB receptor agonist, inhibits the expression of p-CREB and NR2B in the spinal dorsal horn in rats with diabetic neuropathic pain.

    Science.gov (United States)

    Liu, Peng; Guo, Wen-Ya; Zhao, Xiao-Nan; Bai, Hui-Ping; Wang, Qian; Wang, Xiu-Li; Zhang, Ying-Ze

    2014-08-01

    This study aimed to investigate the effect of baclofen, a γ-aminobutyric acid B (GABAB) receptor agonist, on the expression of p-CREB and NR2B in the spinal dorsal horn of rats with diabetic neuropathic pain (DNP). The DNP rats, which were successfully induced with streptozocin, were distributed among 3 groups that were treated with saline (D1 group), baclofen (D2 group), or CGP55845 + baclofen (D3 group) continuously for 4 days. The rats induced with saline and subsequently treated with saline were used as controls (C group). The times for the paw withdrawal threshold and thermal withdrawal latency of the D1 group were lower than those for the C group, and were significantly increased after baclofen treatment, but not when GABA receptor was pre-blocked with CGP55845 (D3 group). Increased protein expression levels of NR2B and p-CREB and mRNA levels of NR2B were found in the D1 group when compared with the controls. Baclofen treatment significantly suppressed their expression, bringing it close to the levels of controls. However, in the D3 group, the expression of p-CREB and NR2B were still significantly higher than that of the controls. Activation of GABAB receptor by baclofen attenuates diabetic neuropathic pain, which may partly be accomplished via down-regulating the expression of p-CREB and NR2B.

  9. Risk factors for baclofen pump infection in children: a multivariate analysis.

    Science.gov (United States)

    Spader, Heather S; Bollo, Robert J; Bowers, Christian A; Riva-Cambrin, Jay

    2016-06-01

    OBJECTIVE Intrathecal baclofen infusion systems to manage severe spasticity and dystonia are associated with higher infection rates in children than in adults. Factors unique to this population, such as poor nutrition and physical limitations for pump placement, have been hypothesized as the reasons for this disparity. The authors assessed potential risk factors for infection in a multivariate analysis. METHODS Patients who underwent implantation of a programmable pump and intrathecal catheter for baclofen infusion at a single center between January 1, 2000, and March 1, 2012, were identified in this retrospective cohort study. The primary end point was infection. Potential risk factors investigated included preoperative (i.e., demographics, body mass index [BMI], gastrostomy tube, tracheostomy, previous spinal fusion), intraoperative (i.e., surgeon, antibiotics, pump size, catheter location), and postoperative (i.e., wound dehiscence, CSF leak, and number of revisions) factors. Univariate analysis was performed, and a multivariate logistic regression model was created to identify independent risk factors for infection. RESULTS A total of 254 patients were evaluated. The overall infection rate was 9.8%. Univariate analysis identified young age, shorter height, lower weight, dehiscence, CSF leak, and number of revisions within 6 months of pump placement as significantly associated with infection. Multivariate analysis identified young age, dehiscence, and number of revisions as independent risk factors for infection. CONCLUSIONS Young age, wound dehiscence, and number of revisions were independent risk factors for infection in this pediatric cohort. A low BMI and the presence of either a gastrostomy or tracheostomy were not associated with infection and may not be contraindications for this procedure.

  10. Severe, Protracted Spasm of Urinary Bladder and Autonomic Dysreflexia Caused by Changing the Suprapubic Catheter in a Cervical Spinal Cord Injury Patient: Treatment by a Bolus Dose and Increased Total Daily Dose of Intrathecal Baclofen

    Science.gov (United States)

    Vaidyanathan, Subramanian; Oo, Tun; Soni, Bakul M.; Hughes, Peter L.; Singh, Gurpreet

    2016-01-01

    BACKGROUND Intrathecal administration of baclofen by implanted pump reduces rigidity and muscle spasms. Its use specifically to control bladder spasms has not been reported. CASE REPORT A tetraplegic patient developed severe, protracted, bladder spasms, abdominal muscles spasms, and high blood pressure after change of suprapubic catheter; nifedipine, diazepam, and paracetamol did not control spasms; bolus dose of baclofen intrathecally produced prompt relief via baclofen pump. CONCLUSION Severe, protracted bladder spasms, abdominal muscles spasms, and autonomic dysreflexia, induced by change of suprapubic catheter in a spinal cord injury patient, were treated successfully by a bolus dose and increased total daily dose of intrathecal baclofen. PMID:28008298

  11. The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain - A detailed case report.

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    Zeman, Adam; Hoefeijzers, Serge; Milton, Fraser; Dewar, Michaela; Carr, Melanie; Streatfield, Claire

    2016-01-01

    We describe a patient in whom long-term, therapeutic infusion of the selective gamma-amino-butyric acid type B (GABAB) receptor agonist, baclofen, into the cerebrospinal fluid (CSF) gave rise to three distinct varieties of memory impairment: i) repeated, short periods of severe global amnesia, ii) accelerated long-term forgetting (ALF), evident over intervals of days and iii) a loss of established autobiographical memories. This pattern of impairment has been reported in patients with temporal lobe epilepsy (TLE), in particular the subtype of Transient Epileptic Amnesia (TEA). The amnesic episodes and accelerated forgetting remitted on withdrawal of baclofen, while the autobiographical amnesia (AbA) persisted. This exceptional case highlights the occurrence of 'non-standard' forms of human amnesia, reflecting the biological complexity of memory processes. It suggests a role for GABAB signalling in the modulation of human memory over multiple time-scales and hints at its involvement in 'epileptic amnesia'.

  12. [Complete remission of consciousness disturbances and spasticity due to a severe subarachnoid hemorrhage after intrathecal baclofen therapy: a case report].

    Science.gov (United States)

    Asahi, Takashi; Kashiwazaki, Daina; Koh, Masaki; Matsumura, Nobuhisa; Kuroda, Satoshi

    2015-03-01

    Typically, intrathecal baclofen therapy(ITB)for spasticity is continuously required because the spasticity can recur if the ITB is stopped. Thus, an infusion pump for the ITB is permanently implanted. Some sporadic cases exhibiting remarkable improvements in their spasticity and consciousness disturbances have been reported after implanting the ITB pump. We experienced a rare case involving removal of the ITB pump after the spasticity resolved and the consciousness disturbances markedly improved. A 15-year-old girl developed a subarachnoid hemorrhage due to rupture of an aneurysm in the right anterior cerebral artery. Her initial Glasgow Coma Scale score was 4(E1V1M2). Trapping of the aneurysm and decompression craniotomy were performed. Subsequently, she underwent a tracheotomy, and a percutaneous gastrostomy(PEG)tube was implanted because of persistent consciousness disturbances. Cranioplasty and lumbar-peritoneal shunt for normal pressure hydrocephalus were performed after 1 month. An ITB pump was implanted to improve the spasticity observed mainly in the lower extremities 61 days after hemorrhage onset. Right hemiparesis remained due to Kernohan's notch. After transfer to the rehabilitation hospital, her consciousness disturbances and spasticity remarkably improved(1.9 to 1.0 and 3.5 to 1.0 on the Ashworth scale for the upper and lower extremities, respectively). The tracheostomy and PEG tubes were removed, and the baclofen dose was gradually reduced. She was completely off baclofen after 7 months, and she was discharged with a short leg brace and a cane for walking. The baclofen pump was then removed. In this case, temporary ITB improved the spasticity and consciousness disturbances.

  13. Kainate-enhanced release of D-(3H)aspartate from cerebral cortex and striatum: reversal by baclofen and pentobarbital

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    Potashner, S.J.; Gerard, D.

    1983-06-01

    A study was made of the actions of the excitant neurotoxin, kainic acid, on the uptake and the release of D-(2,3-3H)aspartate (D-ASP) in slices of guinea pig cerebral neocortex and striatum. The slices took up D-ASP, reaching concentrations of the amino acid in the tissue which were 14-23 times that in the medium. Subsequently, electrical stimulation of the slices evoked a Ca2+-dependent release of a portion of the D-ASP. Kainic acid (10(-5)-10(-3) M) produced a dose-dependent inhibition of D-ASP uptake. The electrically evoked release of D-ASP was increased 1.6-2.0 fold by 10(-5) and 10(-4)M kainic acid. The kainate-enlarged release was Ca2+-dependent. Dihydrokainic acid, an analogue of kainic acid with little excitatory or toxic action, did not increase D-ASP release but depressed D-ASP uptake. Attempts were made to block the action of kainic acid with baclofen and pentobarbital, compounds which depress the electrically evoked release of L-glutamate (L-GLU) and L-aspartate (L-ASP). Baclofen (4 X 10(-6)M), an antispastic drug, and pentobarbital (10(-4)M), an anesthetic agent, each inhibited the electrically evoked release of D-ASP and prevented the enhancement of the release above control levels usually produced by 10(-4)M kainic acid. It is proposed that 10(-5) and 10(-4)M kainic acid may enhance the synaptic release of L-GLU and L-ASP from neurons which use these amino acids as transmitters. This action is prevented by baclofen and pentobarbital. In view of the possibility that cell death in Huntington's disease could involve excessive depolarization of striatal and other cells by glutamate, baclofen might be effective in delaying the loss of neurons associated with this condition.

  14. ACAMPROSATE AND BACLOFEN WERE NOT EFFECTIVE IN THE TREATMENT OF PATHOLOGICAL GAMBLING: PRELIMINARY BLIND RATER COMPARISON STUDY

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    Pinhas N Dannon

    2011-06-01

    Full Text Available Objectives: Pathological gambling (PG is a highly prevalent and disabling impulse control disorder. A range of psychopharmacological options are available for the treatment of PG, including selective serotonin reuptake inhibitors (SSRI, opioid receptor antagonists, anti-addiction drugs and mood stabilizers. In our preliminary study, we examined the efficacy of two anti-addiction drugs, Baclofen and Acamprosate, in the treatment of PG. Materials & Methods: 17 male gamblers were randomly divided into two groups. Each group received one of the two drugs without being blind to treatment. All patients underwent a comprehensive psychiatric diagnostic evaluation and completed a series of semi-structured interviews. During the six months of study, monthly evaluations were carried out to assess improvement and relapses. Relapse was defined as recurrent gambling behavior. Results: None of the 17 patients reached the six months abstinence. One patient receiving Baclofen sustained abstinence for 4 months. 14 patients succeeded in sustaining abstinence for 1-3 months. 2 patients stopped attending monthly evaluations. Conclusion: Baclofen and Acamprosate did not prove efficient in treating pathological gamblers.

  15. Liquid chromatography-tandem mass spectrometry determination of baclofen in various biological samples and application to a pharmacokinetic study.

    Science.gov (United States)

    Kim, Tae Hwan; Shin, Soyoung; Shin, Jeong Cheol; Choi, Jin Ho; Seo, Won Sik; Park, Gi-Young; Kwon, Dong Rak; Yoo, Sun Dong; Lee, Ah-Ram; Joo, Sang Hoon; Min, Byung Sun; Yoo, Won Young; Shin, Beom Soo

    2013-11-01

    Baclofen is a structural analogue of γ-aminobutyric acid (GABA) that has been used for the treatment of spasticity since 1977. This study describes a simple and sensitive LC/MS/MS assay for the quantification of baclofen in rat plasma, urine, as well as various tissue samples. The assay utilized a simple protein precipitation and achieved lower limit of quantification (LLOQ) of 0.25ng/mL for rat plasma and brain samples and 2ng/mL for rat urine, liver and kidney samples. The assay was validated to demonstrate the specificity, linearity, recovery, LLOQ, accuracy, precision, and stability by using matrix matched quality control samples. There is no endogenous or exogenous peaks interfering with the analytes and matrix effects were minimized by optimized separation condition. The assay was linear over a concentration range of 0.25-500ng/mL for rat plasma and brain tissue, and 2-5000ng/mL for rat urine, kidney and liver with correlation coefficients >0.999. The mean intra- and inter-day assay accuracies were 94.6-104.6 and 96.0-103.6%, respectively. The mean intra- and inter-day precisions were 5.71 and 5.70%, respectively. The developed assay was successfully applied to a pharmacokinetic study and examined urinary excretion and tissue distribution of baclofen in rats following intravenous and oral administration.

  16. Pharmacology of intracisternal or intrathecal glycine, muscimol, and baclofen in strychnine-induced thermal hyperalgesia of mice.

    Science.gov (United States)

    Lee, Il Ok; Son, Jin Kook; Lim, Eui-Sung; Kim, Yeon-Soo

    2011-10-01

    Glycine and γ-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABA(A) receptor agonist), baclofen (a GABA(B) receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.

  17. Baclofen effects on alcohol seeking, self-administration and extinction of seeking responses in a within-session design in baboons.

    Science.gov (United States)

    Duke, Angela N; Kaminski, Barbara J; Weerts, Elise M

    2014-01-01

    Baclofen, a gamma-aminobutyric acidB receptor agonist, is currently under investigation as a potential treatment to prevent relapse to drinking in alcohol-dependent persons. In the current study, two groups of baboons were trained under a chained schedule of reinforcement (CSR), with three linked components, which were each correlated with different response requirements and cues. Fulfilling the requirement in the second link initiated the third link where either alcohol (n = 4) or a preferred non-alcoholic beverage (Tang, n = 5) was available for self-administration; failure to complete the response requirement in Link 2 ended the session (no access to alcohol or Tang). Seeking responses in Link 2 were used as indices of the motivational processes thought to be involved in relapse. The effects of baclofen (0.1-2.4 mg/kg) were examined under conditions with alcohol or Tang access and under extinction. Under the CSR, baclofen (1.8 and 2.4 mg/kg) significantly decreased (P baclofen (2.4 mg/kg) reduced Tang self-administration and consumption. Under within-session extinction conditions, baclofen (1.8 and 2.4 mg/kg) facilitated extinction of responding for both alcohol and Tang, particularly during the first 10 minutes of extinction. Baclofen may be effective in reducing craving and alcohol drinking, although the facilitation of extinction and suppression of both alcohol and Tang self-administration by baclofen suggests these effects may be related to a more general suppression of consummatory and conditioned behaviors.

  18. Modulation of TLR3/TLR4 inflammatory signaling by the GABAB receptor agonist baclofen in glia and immune cells: relevance to therapeutic effects in multiple sclerosis

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    Tadhg eCrowley

    2015-07-01

    Full Text Available The GABAB receptor agonist, baclofen, is used to treat muscle tightness and cramping caused by spasticity in a number of disorders including Multiple Sclerosis (MS, but its precise mechanism of action is unknown. Neuroinflammation drives the central pathology in MS and is mediated by both immunoreactive glial cells and invading lymphocytes. Furthermore, a body of data indicates that the Toll-like receptor (TLR family of innate immune receptors is implicated in MS progression. In the present study we investigated whether modulation of GABAB receptors using baclofen can exert anti-inflammatory effects by targeting TLR3 and(or TLR4-induced inflammatory signaling in murine glial cells and human peripheral blood mononuclear cells (PBMCs isolated from healthy control individuals and patients with the relapse-remitting (RR form of MS. TLR3 and TLR4 stimulation promoted the nuclear sequestration of NF-κB and pro-inflammatory cytokine expression in murine glia, while TLR4, but not TLR3, promoted pro-inflammatory cytokine expression in PBMCs isolated from both healthy donors and RR-MS patients. Importantly, this effect was exacerbated in RR-MS patient immune cells. We present further evidence that baclofen dose-dependently attenuated TLR3- and TLR4-induced inflammatory signaling in primary glial cells. Pre-exposure of PBMCs isolated from healthy donors to baclofen attenuated TLR4-induced TNF-α expression, but did not affect TLR4-induced TNF-α expression in RR-MS patient PBMCs. Interestingly, mRNA expression of the GABAB receptor was reduced in PBMCs from RR-MS donors when compared to healthy controls, an effect that might contribute to the differential sensitivity to baclofen seen in healthy and RR-MS patient cells. Overall these findings indicate that baclofen differentially regulates TLR3 and TLR4 signaling in glia and immune cells, and offers insight on the role of baclofen in the treatment of neuroinflammatory disease states including MS.

  19. How should an infected perinephric haematoma be drained in a tetraplegic patient with baclofen pump implanted in the abdominal wall? – A case report

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    Watt John WH

    2002-09-01

    Full Text Available Abstract Background We present a case to illustrate controversies in percutaneous drainage of infected, perinephric haematoma in a tetraplegic patient, who had implantation of baclofen pump in anterior abdominal wall on the same side as perinephric haematoma. Case presentation A 56-year-old male with C-4 tetraplegia had undergone implantation of programmable pump in the anterior abdominal wall for intrathecal infusion of baclofen to control spasticity. He developed perinephric haematoma while he was taking warfarin as prophylactic for deep vein thrombosis. Perinephric haematoma became infected with a resistant strain of Pseudomonas aeruginosa, and required percutaneous drainage. Positioning this patient on his abdomen without anaesthesia, for insertion of a catheter from behind, was not a realistic option. Administration of general anaesthesia in this patient in the radiology department would have been hazardous. Results and Conclusion Percutaneous drainage was carried out by anterior approach under propofol sedation. The site of entry of percutaneous catheter was close to cephalic end of baclofen pump. By carrying out drainage from anterior approach, and by keeping this catheter for ten weeks, we took a risk of causing infection of the baclofen pump site, and baclofen pump with a resistant strain of Pseudomonas aeruginosa. The alternative method would have been to anaesthetise the patient and position him prone for percutaneous drainage of perinephric collection from behind. This would have ensured that the drainage track was far away from the baclofen pump with minimal risk of infection of baclofen pump, but at the cost of incurring respiratory complications in a tetraplegic subject.

  20. Effect of baclofen on liquid and solid gastric emptying in rats Efeito do baclofen no esvaziamento gástrico de líquido e de sólidos em rato

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    Edgard Ferro Collares

    2010-09-01

    Full Text Available CONTEXT: Gamma-aminobutyric acid (GABA is a potent inhibitory neurotransmitter. There is evidence that GABA B receptors located in the dorsal complex and in afferent fibers of the vagus nerve participate in the control of gastrointestinal motility. OBJECTIVE: To assess the intracerebroventricularly (ICV and intravenously (IV effect of baclofen, a GABA B receptor agonist, on liquid and solid gastric emptying in rats. METHODS: Adult male Wistar rats weighing 250-300 g (n = 6-8 animals were used. Gastric emptying of liquid test meals labeled with phenol red was evaluated by the determination of percent gastric retention (%GR 10 and 15 min after orogastric administration of saline and 10% glucose meals, respectively. Baclofen was injected ICV (1 and 2 µg/animal through a tube implanted into the lateral ventricle of the brain and was injected IV (1 and 2 mg/kg into a tail vein. The gastric emptying of liquid was determined 10 or 30 min after ICV and IV baclofen administration, respectively. The gastric emptying of the solid meal was assessed by the determination of percent gastric retention 2 h after the beginning of the ingestion of the habitual ratio by the animal, consumed over a period of 30 min. Baclofen was administered ICV (1 and 2 µg/animal or IV (1 and 2 mg/kg immediately after the end of the ingestion of the solid meal. The control groups received vehicle (sterile saline solution ICV or IV. RESULTS: The group of animals receiving baclofen ICV (2 mg/animal presented a significantly lower (PCONTEXTO: O ácido gama-aminobutírico (GABA é um potente neurotransmissor inibitório. Há evidências que receptores GABA>B localizados no complexo dorsal do vago e em fibras aferentes do nervo vago participam no controle da motricidade gastrointestinal. OBJETIVO: Avaliar o efeito intracerebroventricular (ICV e intravenoso (IV do baclofen, um agonista para receptores GABA B, sobre o esvaziamento gástrico de líquidos e de sólidos em ratos. M

  1. Anxiety status affects nicotine- and baclofen-induced locomotor activity, anxiety, and single-trial conditioned place preference in male adolescent rats.

    Science.gov (United States)

    Falco, Adriana M; McDonald, Craig G; Smith, Robert F

    2014-09-01

    Adolescents have an increased vulnerability to nicotine and anxiety may play a role in the development of nicotine abuse. One possible treatment for anxiety disorders and substance abuse is the GABAB agonist, baclofen. The aim of the present study was to determine the effect of anxiety-like behavior on single-trial nicotine conditioned place preference in adolescent rats, and to assess the action of baclofen. Baclofen was shown to have effects on locomotor and anxiety-like behavior in rats divided into high-anxiety and low-anxiety groups. Baclofen decreased locomotor behavior in high-anxiety rats. Baclofen alone failed to produce differences in anxiety-like behavior, but nicotine and baclofen + nicotine administration were anxiolytic. High- and low-anxiety groups also showed differences in single-trial nicotine-induced place preference. Only high-anxiety rats formed place preference to nicotine, while rats in the low-anxiety group formed no conditioned place preference. These results suggest that among adolescents, high-anxiety individuals are more likely to show preference for nicotine than low-anxiety individuals.

  2. Treatment of severe spacticity in multiple sclerosis by continuous intrathecal baclofen

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    Perić Predrag

    2006-01-01

    Full Text Available Background. Successful treatment of severe spasticity represents an imperative of symptomatic therapy of multiple sclerosis (MS due to a significant improvement of physical, psychic and social rehabilitation of MS patients, as well as a longterm cost savings for the additional treatments of conditions arising from uncontrolled severe spasticity. Continuous intrathecal administration of baclofen (ITB, using a subcutaneously implanted programmable infusion pump, is a minimally invasive, reversible method for the treatment of severe diffuse spasticity of the spinal origin. Case report. The first two cases in our country, treated by ITB due to severe spasticity caused by MS, were reported. Despite the local complications of surgical wound healing above the implanted components of the ITB-system in one patient, the optimal reduction of spasticity the with complete elimination of spastic pain was obtained in both patients. Conclusion. Our initial experiences confirmed ITB as a safe and effective therapeutical option for the treatment of intractable spasticity in patients with MS. Major prerequisites for this were adequate patient selection and good control of the basic disease. The use of the minimal invasive implantation technique and the experience in choosing of the adequate ITB-system components, could successfully prevent the occurrence of local complications related to the impaired healing of the ITB-system implantation site.

  3. Enantiodifferentiation of chiral baclofen by β-cyclodextrin using capillary electrophoresis: A molecular modeling approach

    Science.gov (United States)

    Suliman, FakhrEldin O.; Elbashir, Abdalla A.

    2012-07-01

    Using capillary electrophoresis baclofen (BF) enantiomers were separated only in the presence of β-cyclodextrin (βCD) as a chiral selector when added to the background electrolyte. Proton nuclear magnetic resonance and electrospray ionization mass spectrometry (ESI-MS) techniques were used to determine the structure of the BF-βCD inclusion complexes. From the MS data BF was found to form a 1:1 complex with α- and βCD, while the NMR data suggest location of the aromatic ring of BF into the cyclodextrin cavity. A molecular modeling study, using the semiempirical PM6 calculations was used to investigate the mechanism of enantiodifferentiation of BF with cyclodextrins. Optimization of the structures of the complexes by PM6 method indicated that separation is obtained in the presence of β-CD due to a large binding energy difference (ΔΔE) of 46.8 kJ mol-1 between S-BF-βCD and R-BF-βCD complexes. In the case of αCD complexes ΔΔE was 1.3 kJ mol-1 indicating poor resolution between the two enantiomers. Furthermore, molecular dynamic simulations show that the formation of more stable S-BF-βCD complex compared to R-BF-β-CD complex is primarily due to differences in intermolecular hydrogen bonding.

  4. Validated Method for the Quantification of Baclofen in Human Plasma Using Solid-Phase Extraction and Liquid Chromatography-Tandem Mass Spectrometry.

    Science.gov (United States)

    Nahar, Limon Khatun; Cordero, Rosa Elena; Nutt, David; Lingford-Hughes, Anne; Turton, Samuel; Durant, Claire; Wilson, Sue; Paterson, Sue

    2016-03-01

    A highly sensitive and fully validated method was developed for the quantification of baclofen in human plasma. After adjusting the pH of the plasma samples using a phosphate buffer solution (pH 4), baclofen was purified using mixed mode (C8/cation exchange) solid-phase extraction (SPE) cartridges. Endogenous water-soluble compounds and lipids were removed from the cartridges before the samples were eluted and concentrated. The samples were analyzed using triple-quadrupole liquid chromatography-tandem mass spectrometry (LC-MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous quantification and confirmation. The assay was linear from 25 to 1,000 ng/mL (r(2) > 0.999; n = 6). Intraday (n = 6) and interday (n = 15) imprecisions (% relative standard deviation) were baclofen (10 and 60 mg) on nonconsecutive days were analyzed to demonstrate method applicability.

  5. The involvement of NMDA receptor/NO/cGMP pathway in the antidepressant like effects of baclofen in mouse force swimming test.

    Science.gov (United States)

    Khan, Muhammad Imran; Ostadhadi, Sattar; Zolfaghari, Samira; Ejtemaei Mehr, Shahram; Hassanzadeh, Gholamreza; Dehpour, Ahmad-Reza

    2016-01-26

    In the current study, the involvement of N-methyl-d-aspartate receptor (NMDAR) and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system in the antidepressant-like effects of baclofen was evaluated by using animal model in forced swimming test. Followed by an open field test for the evaluation of locomotor activity, the immobility time for mice in force swimming test was recorded. Only the last four min was analyzed. Administration of Baclofen (0.5 and 1mg/kg, i.p.) reduced the immobility interval in the FST. Prior administration of l-arginine (750mg/kg, i.p.,) a nitric oxide synthase substrate or sildenafil (5mg/kg, i.p.) a phosphodiesterase 5 into mice suppressed the antidepressant-like activity of baclofen (1mg/kg, i.p.).Co-treatment of 7-nitroindazole (50mg/kg, i.p.,) an inhibitor of neuronal nitric oxide synthase, L-NAME (10mg/kg, i.p.,) a non-specific inhibitor of nitric oxide synthase or MK-801 (0.05mg/kg, i.p.) an NMDA receptor antagonist with subeffective dose of baclofen (0.1mg/kg, i.p.), reduced the immobility time in the FST as compared to the drugs when used alone. Co-administrated of lower doses of MK-801 (0.01mg/kg) or l-NAME (1mg/kg) failed to effect immobility time however, simultaneous administration of these two agents in same dose with subeffective dose of baclofen (0.1mg/kg, i.p.), minimized the immobility time in the FST. Thus, our results support the role of NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant-like action of baclofen.

  6. Intra-nucleus accumbens shell injections of R(+)- and S(-)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice.

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    Kasten, Chelsea R; Boehm, Stephen L

    2014-10-01

    The GABAB agonist baclofen has been widely researched clinically and preclinically as a treatment of alcohol use disorders (AUDs). However, the efficacy of baclofen remains uncertain. The clinically used racemic compound can be separated into separate enantiomers. These enantiomers have produced different profiles in behavioral assays, with the S- compound often being ineffective compared to the R- compound, or the S- compound antagonizing the effects of the R- compound. We have previously demonstrated that the R(+)-baclofen enantiomer decreases binge-like ethanol intake in the Drinking-in-the-Dark (DID) paradigm, whereas the S(-)-baclofen enantiomer increases ethanol intake. One area implicated in drug abuse is the nucleus accumbens shell (NACsh).The current study sought to define the role of the NACsh in the enantioselective effects of baclofen on binge-like ethanol consumption by directly microinjecting each enantiomer into the structure. Following bilateral cannulation of the NACsh, C57Bl/6J mice were given 5 days of access to ethanol or saccharin for 2h, 3h into the dark cycle. On Day 5 mice were given an injection of aCSF, 0.02 R(+)-, 0.04R(+)-, 0.08 S(-)-, or 0.16 S(-)-baclofen (μg/side dissolved in 200nl of aCSF). It was found that the R(+)-baclofen dose-dependently decreased ethanol consumption, whereas the high S(-)-baclofen dose increased ethanol consumption, compared to the aCSF group. Saccharin consumption was not affected. These results further confirm that GABAB receptors and the NACsh shell are integral in mediating ethanol intake. They also demonstrate that baclofen displays bidirectional, enantioselective effects which are important when considering therapeutic uses of the drug.

  7. Long term effect (more than five years) of intrathecal baclofen on impairment, disability, and quality of life in patients with severe spasticity of spinal origin

    NARCIS (Netherlands)

    Zahavi, A; Geertzen, JHB; Middel, B; Staal, M; Rietman, JS

    2004-01-01

    Objectives: To evaluate long term change in impairment, disability, and health related functional status in patients with severe spasticity who received intrathecal baclofen. Methods: A long term ( more than five years) observational longitudinal follow up study assessing 21 patients who received in

  8. [Scintigraphic imaging in the diagnosis of failed intrathecal baclofen therapy: a case report of a 7-year-old boy with ventriculoperitoneal shunt].

    Science.gov (United States)

    Shibata, Akiko; Yamamoto, Mariko; Watanabe, Yu; Terashima, Hiroshi; Kashii, Hirofumi; Kubota, Masaya; Morota, Nobuhito

    2015-09-01

    Intrathecal baclofen (ITB) therapy is popular for the management of intractable spasticity. In 2007, the indications of ITB therapy expanded to include spasticity of children in Japan. In this report, we assessed the utility of radioisotopic scintigraphy in the diagnosis of failed ITB therapy. A 7-year-old boy with schizencephaly, hydrocephalus, and spastic quadriplegia had an ITB pump implanted. In his infancy, he had undergone ventriculoperitoneal shunt implantation. One month after the ITB operation, the ITB therapeutic effect diminished. Several examinations confirmed that the pump function was normal and catheter failure had not occurred. However, radioisotopic scintigraphy revealed that the baclofen had been washed out to blood circulation more rapidly than is typically observed. We considered two possible causes for this; obstruction of the cerebrospinal space due to kyphosis and excessive washout of celebrospinal fluid through the ventriculoperitoneal shunt. The catheter was moved to a more caudal site surgically, and his spasticity improved. The use of radioisotopic scintigraphy to identify the distribution of baclofen is an effective technique for investigation of baclofen pump system malfunction.

  9. Effect of intrathecal baclofen delivered by an implanted programmable pump on health related quality of life in patients with severe spasticity

    NARCIS (Netherlands)

    Middel, B.; Kuipers-Upmeijer, H.; Bouma, J.; Staal, M.J.; Oenema, D.G.; Postma, T.J.B.M.; Terpstra, S.; Stewart, R.

    1997-01-01

    Objectives-To compare clinical effectiveness and health related quality of life in patients with severe spasticity who received intrathecal baclofen or a placebo. Methods-In a double blind, randomised, multicentre trial 22 patients were followed up during 13 weeks and subsequently included in a 52 w

  10. The gamma-aminobutyric acid type B (GABAB receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens

    Directory of Open Access Journals (Sweden)

    Fu Zhenyu

    2012-07-01

    Full Text Available Abstract Background Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. Methods We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. Results The present study demonstrated that morphine challenge (3 mg/kg, s.c. obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Conclusions Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.

  11. Effect of baclofen combined with neural facilitation technique on the reduction of muscular spasm in patients with spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    BACKGROUND: Recent researches have demonstrated that baclofen is a commonly central anti-spasm drug. In addition, neural facilitation technique based on nerve development and neurophysiology is widely used for rehabilitation training of motor disorder after central nerve injury. However, whether baclofen combining with neural facilitation technique can relieve muscular spasm after spinal cord injury needs further studies.OBJECTIVE: To observe the effect of baclofen combining with neural facilitation technique on decreasing muscular tension in two lower extremities after spinal cord injury.DESIGN: Randomized controlled study.SETTING: Departments of Rehabilitation and Orthopaedics, the Third Affiliated Hospital of Guangzhou Medical College.PARTICIPANTS: A total of 28 patients with spinal cord injury, including 17 males and 11 females, whose age ranged from 31 to 71 years, were selected from Departments of Rehabilitation and Orthopaedics, the Third Affiliated Hospital of Guangzhou Medical College from March 2005 to September 2006. The illness course ranged from 22 to 54 days and the mean course was (38 ± 8) days. All patients were diagnosed as the first onset and the increase of extensor muscular tension in two lower extremities after thoracic vertebra injury by using spine MR or CT examination. Informed consents were obtained from all the patients.METHODS: All 28 patients who had upper motor neuronal paralysis in two lower extremities after spinal cord injury in thoracic vertebra region were randomly divided into treatment group and control group with 14 cases in each group. Patients in both groups received routine therapy, while those in the treatment group were treated with oral baclofen (the beginning dosage: 5 mg/time; three times per day, 5 mg was increased every three days; the maximal dosage was 60 mg/day; 6 weeks in total) (made in Weicai Pharmaceutical Co., Ltd.;tablet; batch number: HC20040029) combining with neural facilitation technique, which accorded

  12. Baclofen alters gustatory discrimination capabilities and induces a conditioned taste aversion (CTA

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    Wilson Gina N

    2011-12-01

    Full Text Available Abstract Background Studies intending to measure drug-induced changes in learning and memory are challenged to parse out the effects of drugs on sensory, motor, and associative systems in the brain. In the context of conditioned taste aversion (CTA, drugs that alter the sensorium of subjects and affect their ability to taste and/or feel malaise may limit the ability of investigators to make conclusions about associative effects of these substances. Since the GABAergic system is implicated in inhibition, the authors were hopeful to use the GABA agonist, baclofen (BAC, to enhance extinction of a CTA, but first a preliminary evaluation of BAC's peripheral effects on animals' sensorium had to be completed due to a lack of published literature in this area. Findings Our first experiment aimed to evaluate the extent to which the GABAB agonist, BAC, altered the ability of rats to differentiate between 0.3% and 0.6% saccharin (SAC in a two bottle preference test. Here we report that 2 or 3 mg/kg (i.p. BAC, but not 1 mg/kg BAC, impaired animals' gustatory discrimination abilities in this task. Furthermore, when SAC consumption was preceded by 2 or 3 mg/kg (i.p. BAC, rats depressed their subsequent SAC drinking. A second experiment evaluated if the suppression of SAC and water drinking (revealed in Experiment 1 was mediated by amnesiac effects of BAC or whether BAC possessed US properties in the context of the CTA paradigm. The time necessary to reach an asymptotic level of CTA extinction was not significantly different in those animals that received the 3 mg/kg dose of BAC compared to more conventionally SAC + lithium chloride (LiCl, 81 mg/kg conditioned animals. Conclusions Our findings were not consistent with a simple amnesia-of-neophobia explanation. Instead, results indicated that 2 and 3 mg/kg (i.p. BAC were capable of inducing a CTA, which was extinguishable via repeated presentations of SAC only. Our data indicate that, depending on the dose, BAC

  13. Baclofen ameliorates spatial working memory impairments induced by chronic cerebral hypoperfusion via up-regulation of HCN2 expression in the PFC in rats.

    Science.gov (United States)

    Luo, Pan; Chen, Cheng; Lu, Yun; Fu, TianLi; Lu, Qing; Xu, Xulin; Li, Changjun; He, Zhi; Guo, Lianjun

    2016-07-15

    Chronic cerebral hypoperfusion (CCH) causes memory deficits and increases the risk of vascular dementia (VD) through several biologically plausible pathways. However, whether CCH causes prefrontal cortex (PFC)-dependent spatial working memory impairments and Baclofen, a GABAB receptor agonist, could ameliorate the impairments is still not clear especially the mechanisms underlying the process. In this study, rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO) to induce CCH. Two weeks later, rats were treated with 25mg/kg Baclofen (intraperitioneal injection, i.p.) for 3 weeks. Spatial working memory was evaluated in a Morris water maze using a modified delayed matching-to-place (DMP) procedure. Western blotting and immunohistochemistry were used to quantify the protein levels and protein localization. Our results showed that 2VO caused striking spatial working memory impairments, accompanied with a decreased HCN2 expression in PFC, but the protein levels of protein gene product 9.5 (PGP9.5, a neuron specific protein), glial fibrillary acidic protein (GFAP), synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), parvalbumin (PV) and HCN1 were not distinguishably changed as compared with sham-operated rats. Baclofen treatment significantly improved the spatial working memory impairments caused by 2VO, accompanied with a reversion of 2VO-induced down-regulation of HCN2. Furthermore, there was a co-localization of HCN2 subunits and parvalbumin-positive neurons in PFC. Therefore, HCN2 may target inhibitory interneurons that is implicated in working memory processes, which may be a possible mechanism of the up-regulation of HCN2 by Baclofen treatment that reliefs spatial working memory deficits in rats with CCH.

  14. General, kappa, delta and mu opioid receptor antagonists mediate feeding elicited by the GABA-B agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats: reciprocal and regional interactions.

    Science.gov (United States)

    Miner, Patricia; Shimonova, Lyudmila; Khaimov, Arthur; Borukhova, Yaffa; Ilyayeva, Ester; Ranaldi, Robert; Bodnar, Richard J

    2012-03-14

    Food intake is significantly increased following administration of agonists of GABA and opioid receptors into the nucleus accumbens shell (NACs) and ventral tegmental area (VTA). GABA-A or GABA-B receptor antagonist pretreatment within the VTA or NACs differentially affects mu-opioid agonist-induced feeding elicited from the same site. Correspondingly, general or selective opioid receptor antagonist pretreatment within the VTA or NACs differentially affects GABA agonist-induced feeding elicited from the same site. Regional interactions have been evaluated in feeding studies by administering antagonists in one site prior to agonist administration in a second site. Thus, opioid antagonist-opioid agonist and GABA antagonist-GABA agonist feeding interactions have been identified between the VTA and NACs. However, pretreatment with GABA-A or GABA-B receptor antagonists in the VTA failed to affect mu opioid agonist-induced feeding elicited from the NACs, and correspondingly, these antagonists administered in the NACs failed to affect mu opioid-induced feeding elicited from the VTA. To evaluate whether regional and reciprocal VTA and NACs feeding interactions occur for opioid receptor modulation of GABA agonist-mediated feeding, the present study examined whether feeding elicited by the GABA-B agonist, baclofen microinjected into the NACs was dose-dependently blocked by pretreatment with general (naltrexone: NTX), mu (beta-funaltrexamine: BFNA), kappa (nor-binaltorphamine: NBNI) or delta (naltrindole: NTI) opioid antagonists in the VTA, and correspondingly, whether VTA baclofen-induced feeding was dose-dependently blocked by NACs pretreatment with NTX, BFNA, NBNI or NTI in rats. Bilateral pairs of cannulae aimed at the VTA and NACs were stereotaxically implanted in rats, and their food intakes were assessed following vehicle and baclofen (200 ng) in each site. Baclofen produced similar magnitudes of increased food intake following VTA and NACs treatment. Baclofen

  15. Anticonvulsant effects of structurally diverse GABA(B) positive allosteric modulators in the DBA/2J audiogenic seizure test: Comparison to baclofen and utility as a pharmacodynamic screening model.

    Science.gov (United States)

    Brown, Jordan W; Moeller, Achim; Schmidt, Martin; Turner, Sean C; Nimmrich, Volker; Ma, Junli; Rueter, Lynne E; van der Kam, Elizabeth; Zhang, Min

    2016-02-01

    The GABA(B) receptor has been indicated as a promising target for multiple CNS-related disorders. Baclofen, a prototypical orthosteric agonist, is used clinically for the treatment of spastic movement disorders, but is associated with unwanted side-effects, such as sedation and motor impairment. Positive allosteric modulators (PAM), which bind to a topographically-distinct site apart from the orthosteric binding pocket, may provide an improved side-effect profile while maintaining baclofen-like efficacy. GABA, the major inhibitory neurotransmitter in the CNS, plays an important role in the etiology and treatment of seizure disorders. Baclofen is known to produce anticonvulsant effects in the DBA/2J mouse audiogenic seizure test (AGS), suggesting it may be a suitable assay for assessing pharmacodynamic effects. Little is known about the effects of GABA(B) PAMs, however. The studies presented here sought to investigate the AGS test as a pharmacodynamic (PD) screening model for GABA(B) PAMs by comparing the profile of structurally diverse PAMs to baclofen. GS39783, rac-BHFF, CMPPE, A-1295120 (N-(3-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide), and A-1474713 (N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide) all produced robust, dose-dependent anticonvulsant effects; a similar profile was observed with baclofen. Pre-treatment with the GABA(B) antagonist SCH50911 completely blocked the anticonvulsant effects of baclofen and CMPPE in the AGS test, indicating such effects are likely mediated by the GABA(B) receptor. In addition to the standard anticonvulsant endpoint of the AGS test, video tracking software was employed to assess potential drug-induced motor side-effects during the acclimation period of the test. This analysis was sensitive to detecting drug-induced changes in total distance traveled, which was used to establish a therapeutic index (TI = hypoactivity

  16. Success With Extended-Infusion Meropenem After Recurrence of Baclofen Pump-Related Achromobacter Xylosoxidans Meningitis in an Adolescent.

    Science.gov (United States)

    Nichols, Kristen R; Knoderer, Chad A; Jackson, Nicholas G; Manaloor, John J; Christenson, John C

    2015-08-01

    A 13-year-old female experienced a recurrence of baclofen pump-related central nervous system (CNS) infection caused by Achromobacter, despite absence of retained foreign material. Due to the failure of meropenem (120 mg/kg/d in divided doses every 8 hours and infused over 30 minutes) in the initial infection, the dose was infused over 4 hours during the recurrence. Meropenem is an antibiotic for which efficacy is time dependent, and 4-hour versus 30-minute infusions have been shown to prolong the time the concentration of the antibiotic exceeds the minimum inhibitory concentration (MIC) of the organism at the site of infection (T>MIC). Meropenem serum concentrations were obtained and indicated that T>MIC was at least 75% of the dosing interval. Our patient improved with no noted recurrences or adverse effects on the extended-infusion meropenem regimen. Utilization of extended-infusion beta-lactam dosing whenever possible in the treatment of serious infections caused by gram-negative organisms should be considered, as this dosing appears to be safe and improves the probability of achieving pharmacokinetic/pharmacodynamic goals.

  17. Efficient Synthesis of β-Aryl-γ-lactams and Their Resolution with (S-Naproxen: Preparation of (R- and (S-Baclofen

    Directory of Open Access Journals (Sweden)

    Iris J. Montoya-Balbás

    2015-12-01

    Full Text Available An efficient synthesis of enantiomerically-pure β-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of β-aryl-γ-lactams with (S-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R- and (S-Baclofen hydrochloride.

  18. Comparison between an Ascenda and a silicone catheter in intrathecal baclofen therapy in pediatric patients: analysis of complications.

    Science.gov (United States)

    Motta, Francesco; Antonello, Clara Eleonora

    2016-10-01

    OBJECTIVE In this single-center study the authors investigated the complications occurring before and after the introduction of the new Ascenda intrathecal catheter (Medtronic Inc.) in pediatric patients treated with intrathecal baclofen therapy (ITB) for spasticity and/or dystonia. METHODS This was a retrospective review of 508 children who had received ITB, 416 with silicone catheters in the 13 years between September 1998 and September 2011 and 92 with Ascenda catheters in the 3 years between September 2011 and August 2014. The authors evaluated major complications such as infections, CSF leaks treated, and problems related to the catheter or pump, and they compared the 2 groups of patients who had received either a silicone catheter or an Ascenda catheter implant. RESULTS One hundred twenty patients in the silicone group (29%) and 1 patient in the Ascenda group (1.1%; p < 0.001) had a major complication. In the silicone group 23 patients (5.5%) were affected by CSF leakage and 75 patients (18%) experienced 82 catheter-related events, such as occlusion, dislodgment, disconnection, or breakage, which required catheter replacement. In the Ascenda group, only 1 patient (1.1%) was affected by CSF leakage. CONCLUSIONS To the authors' knowledge, this study is the first in the literature to compare the performance of the new Ascenda catheter, introduced in 2011, with the traditional silicone catheter for intrathecal drug infusion. In their analysis, the authors found that the Ascenda catheter can reduce major complications related to the catheter after ITB pump implantation. Further investigation is necessary to expand on and confirm their results.

  19. An algorithmic approach to the management of unrecognized hydrocephalus in pediatric candidates for intrathecal baclofen pump implantation

    Science.gov (United States)

    Hanak, Brian W.; Tomycz, Luke; Oxford, Robert G.; Hooper, Erin; Apkon, Susan D.; Browd, Samuel R.

    2016-01-01

    Background: Complications of intrathecal baclofen (ITB) pump implantation for treatment of pediatric patients with spasticity and dystonia associated with cerebral palsy remain unacceptably high. To address the concern that some patients may have underlying arrested hydrocephalus, which is difficult to detect clinically because of a low baseline level of neurological function, and may contribute to the high rates of postoperative cerebrospinal fluid leak, wound breakdown, and infection associated with ITB pump implantation, the authors implemented a standardized protocol including mandatory cranial imaging and assessment of intracranial pressure (ICP) by lumbar puncture prior to ITB pump implantation. Methods: A retrospective case series of patients considered for ITB pump implantation between September 2012 and October 2014 at Seattle Children's Hospital is presented. All patients underwent lumbar puncture under general anesthesia prior to ITB pump implantation and, if the opening pressure was greater than 21 cmH2O, ITB pump implantation was aborted and alternative management options were presented to the patient's family. Results: Eighteen patients were treated during the study time period. Eight patients (44.4%) who had ICPs in excess of 21 cmH2O on initial LP were identified. Eleven patients (61.1%) ultimately underwent ITB pump implantation (9/10 in the “normal ICP” group and 2/8 in the “elevated ICP” group following ventriculoperitoneal shunt placement), without any postoperative complications. Conclusions: Given the potentially high rate of elevated ICP and arrested hydrocephalus, the authors advocate pre-implantation assessment of ICP under controlled conditions and a thoughtful consideration of the neurosurgical management options for patients with elevated ICP. PMID:28168091

  20. Bladder stones – red herring for resurgence of spasticity in a spinal cord injury patient with implantation of Medtronic Synchromed pump for intrathecal delivery of baclofen – a case report

    Directory of Open Access Journals (Sweden)

    Singh Gurpreet

    2003-03-01

    Full Text Available Abstract Background Increased spasms in spinal cord injury (SCI patients, whose spasticity was previously well controlled with intrathecal baclofen therapy, are due to (in order of frequency drug tolerance, increased stimulus, low reservoir volume, catheter malfunction, disease progression, human error, and pump mechanical failure. We present a SCI patient, in whom bladder calculi acted as red herring for increased spasticity whereas the real cause was spontaneous extrusion of catheter from intrathecal space. Case Presentation A 44-year-old male sustained a fracture of C5/6 and incomplete tetraplegia at C-8 level. Medtronic Synchromed pump for intrathecal baclofen therapy was implanted 13 months later to control severe spasticity. The tip of catheter was placed at T-10 level. The initial dose of baclofen was 300 micrograms/day of baclofen, administered by a simple continuous infusion. During a nine-month period, he required increasing doses of baclofen (875 micrograms/day to control spasticity. X-ray of abdomen showed multiple radio opaque shadows in the region of urinary bladder. No malfunction of the pump was detected. Therefore, increased spasticity was attributed to bladder stones. Electrohydraulic lithotripsy of bladder stones was carried out successfully. Even after removal of bladder stones, this patient required further increases in the dose of intrathecal baclofen (950, 1050, 1200 and then 1300 micrograms/day. Careful evaluation of pump-catheter system revealed that the catheter had extruded spontaneously and was lying in the paraspinal space at L-4, where the catheter had been anchored before it entered the subarachnoid space. A new catheter was passed into the subarachnoid space and the tip of catheter was located at T-8 level. The dose of intrathecal baclofen was decreased to 300 micrograms/day. Conclusion Vesical calculi acted as red herring for resurgence of spasticity. The real cause for increased spasms was spontaneous extrusion

  1. Regulation by divalent cations of /sup 3/H-baclofen binding to GABA/sub B/ sites in rat cerebellar membranes

    Energy Technology Data Exchange (ETDEWEB)

    Kato, K.; Goto, M.; Fukuda, H.

    1983-02-21

    When investigating the effects of divalent cations (Mg/sup 2 +/, Ca/sup 2 +/, Sr/sup 2 +/, Ba/sup 2 +/, Mn/sup 2 +/ and Ni/sup 2 +/) on /sup 3/H-baclofen binding to rat cerebellar synaptic membranes, we found that the specific binding of /sup 3/H-baclofen was not only dependent on divalent cations, but was increased dose-dependently in the presence of these cations. The effects were in the following order of potency: Mn/sup 2 +/ approx. = Ni/sup 2 +/ > Mg/sup 2 +/ > Ca/sup 2 +/ > Sr/sup 2 +/ > Ba/sup 2 +/. Scatchard analysis of the binding data revealed a single component of the binding sites in the presence of 2.5 mM MgCl/sub 2/, 2.5 mM CaCl/sub 2/ or 0.3 mM MnCl/sub 2/ whereas two components appeared in the presence of 2.5 mM MnCl/sub 2/ or 1 mM NiCl/sub 2/. In the former, divalent cations altered the apparent affinity (K/sub d/) without affecting density of the binding sites (B/sub max/). In the latter, the high-affinity sites showed a higher affinity and lower density of the binding sites than did the single component of the former. As the maximal effects of four cations (Mg/sup 2 +/, Ca/sup 2 +/, Mn/sup 2 +/, and Ni/sup 2 +/) were not additive, there are probably common sites of action of these divalent cations. Among the ligands for GABA/sub B/ sites, the affinity for (-), (+) and (+/-)baclofen, GABA and ..beta..-phenyl GABA increased 2 - 6 fold in the presence of 2.5 mM MnCl/sub 2/, in comparison with that in HEPES-buffered Krebs solution (containing 2.5 mM CaCl/sub 2/ and 1.2 mM MgSO/sub 4/), whereas that for muscimol was decreased to one-fifth. Thus, the affinity of GABA/sub B/ sites for its ligands is probably regulated by divalent cations, through common sites of action.

  2. Method for recording spinal reflexes in mice: effects of thyrotropin-releasing hormone, DOI, tolperisone and baclofen on monosynaptic spinal reflex potentials.

    Science.gov (United States)

    Okada, H; Honda, M; Ono, H

    2001-05-01

    Mice were used to record the spinal reflex potentials and to examine the effects of some drugs upon them. In anesthetized mice, laminectomy was performed in the lumbo-sacral region, and monosynaptic reflex potential (MSR) and polysynaptic reflex potential were recorded from the L5 ventral root after stimulation of the L5 dorsal root. Thyrotropin-releasing hormone (TRH) and 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) produced transient and long-lasting increases in the MSR amplitude, respectively. Tolperisone hydrochloride and baclofen produced transient and long-lasting MSR depressions, respectively. These results show that mice can be used to record spinal reflex potentials, and that it may be possible to study the spinal cord function of mutant and knockout mice using this method.

  3. Clinical Use of Baclofen at the late stage of stroke%巴氯芬在中风后期的临床应用研究

    Institute of Scientific and Technical Information of China (English)

    秦绍森; 张晓燕; 罗盛; 王作为; 刘明; 陈海波

    2001-01-01

    目的:观察国产巴氯芬对中风后期伴肌张力增高患者的治疗效果及不良反应。方法:门诊就诊病程3月以上的中风伴肌张力增高的患者30例予以巴氯芬口服治疗。起始剂量为5mg,每日1次, 3天后增加5mg,最大剂量每日小于80mg,维持治疗8周。服药前、后4周、 8周检查血尿常规及肝肾功能。肌张力测定按国际通用的Ashworth评分,与治疗前相比肌张力恢复正常为痊愈。肌张力减低2级以上为显效,减低1级为有效。结果:除1例脱落外,余29例患者中显效9例,有效16例,总有效率为86.2%,而且未见明显毒副作用。结论:巴氯芬对脑血管病患者的偏瘫痉挛有较好效果,有利于偏瘫肢体的功能锻炼及康复。%Objective:To assess the efficacy and side effect of Baclofen in treating patients with hypertonia at the late stage of stroke. Methods: Thorty patients with hypertonia at the late stage of strole were treated with Baclofen (initial dosage:15mg/d, plus 5mg/d every 3 days, maximal dose: <80mg/d) for 8 weeks. Blood and Urine routine test, and hepatic and renal function were monitored before and 4 , 8 weeks after the treatment. Muscle tone was assessed according to Ashworth score. Complete recovery was considered if muscle tone ncrmdized, excellent efficacy if muscle tone decreased by two degrees, and good efficacy if muscle tone decreased by one degree. Results:Nine patients were found to have the decrease of muscle tone for more than 2 degrees, 16 patients for one degree. The total efficacy rate was 86.2%. The results indicate than Baclofen is effective in relieving suffered-limb spasm sfter cerebral vascular disorders. No side effect was observed. Conclusion: Baclofen is effective to patients with hypertonia at the late stage of stroke. It is beneficial to the rehabilitation and suffered-limb exercise.

  4. HPLC enantioseparation of racemic bupropion, baclofen and etodolac: modification of conventional ligand exchange approach by pre-column formation of chiral ligand exchange complexes.

    Science.gov (United States)

    Singh, Manisha; Bhushan, Ravi

    2016-11-01

    Separation of racemic mixture of (RS)-bupropion, (RS)-baclofen and (RS)-etodolac, commonly marketed racemic drugs, has been achieved by modifying the conventional ligand exchange approach. The Cu(II) complexes were first prepared with a few l-amino acids, namely, l-proline, l-histidine, l-phenylalanine and l-tryptophan, and to these was introduced a mixture of the enantiomer pair of (RS)-bupropion, or (RS)-baclofen or (RS)-etodolac. As a result, formation of a pair of diastereomeric complexes occurred by 'chiral ligand exchange' via the competition between the chelating l-amino acid and each of the two enantiomers from a given pair. The diastereomeric mixture formed in the pre-column process was loaded onto HPLC column. Thus, both the phases during chromatographic separation process were achiral (i.e. neither the stationary phase had any chiral structural feature of its own nor did the mobile phase have any chiral additive). Separation of diastereomers was successful using a C18 column and a binary mixture of MeCN and TEAP buffer of pH 4.0 (60:40, v/v) as mobile phase at a flow rate of 1 mL/min and UV detection at 230 nm for (RS)-Bup, 220 nm for (RS)-Bac and 223 nm for (RS)-Etd. Baseline separation of the two enantiomers was obtained with a resolution of 6.63 in <15 min. Copyright © 2016 John Wiley & Sons, Ltd.

  5. The therapeutic effect comparative study of botulinum toxin A and baclofen in hemifacial spasm%A型肉毒毒素与巴氯芬治疗偏侧面肌痉挛的疗效对比

    Institute of Scientific and Technical Information of China (English)

    辛晋敏

    2012-01-01

    Objective To compare the therapeutic effect of local injection of botulinum toxin A (BTXA) and oral baclofen in hemifacial spasm (HFS).Methods Sixty-six patients with HFS were divided into BTXA treatment group (33 patients) and baclofen treatment group (33 patients) by random digits table.The patients in BTXA treatment group was given local multipoint target muscle injection of BTXA,and the patients in baclofen treatment group was given oral baclofen.The therapeutic effect was assessed after treatment of 2 weeks and 4 weeks.Results The scores of spasticity before treatment had no significant difference between two groups (P > 0.05).After treatment of 2 weeks and 4 weeks,the scores of spasticity in BTXA treatment group and baclofen treatment group were significantly decreased [BTXA treatment group:(1.80 ±0.70),(1.57 ± 0.17) scores vs.(3.15 ±0.43) scores;baclofen treatment group:(2.14 ±0.60),(1.14 ± 0.70) scores vs.(3.00 ± 0.48) scores] (P < 0.01).The scores of spasticity in BTXA treatment group after treatment of 2 weeks and 4 weeks were significantly lower than those in baclofen treatment group (P <0.05 or <0.01).After treatment of 4 weeks,the grades of spasticity between two groups had significant difference (P <0.05).The rate of adverse reaction in BTXA treatment group [15.15% (5/33)] was significantly lower than that in baclofen treatment group [51.52% (17/33)] (P < 0.01).Conclusions Local injection of BTXA and low dose oral baclofen in treatment of HFS can reach the obvious relief.But BTXA treatment has rapid onset,Iess adverse reaction and high compliance of the patients,and also symptoms improve more completely after BTXA treatment.BTXA can be used as preferred method of treating HFS.%目的 比较局部注射A型肉毒毒素(BTXA)与口服巴氯芬治疗偏侧面肌痉挛(HFS)的效果.方法 将2010年7月至2012年6月确诊HFS患者66例按随机数字表法分为BTXA治疗组和巴氯芬治疗组,对BTXA治疗组33例患者进行

  6. Curative Effect Observation of Baclofen Treating Abnormal Subjective Sensation after Stroke%巴氯芬治疗脑卒中后主观感觉异常的疗效观察

    Institute of Scientific and Technical Information of China (English)

    马琳; 毛永军; 薛韬

    2016-01-01

    目的:观察巴氯芬治疗脑卒中后主观感觉异常的效果。方法选择我院住院的伴有主观感觉异常的脑卒中患者,随机分为对照组20例,采用常规治疗,治疗组20例,采用常规治疗基础上加用巴氯芬治疗。治疗共14天,比较两组间治疗后主观感觉异常恢复的总有效率及平均起效时间。结果①治疗组的总有效率为95%,对照组总有效率45%,两组间比较差异有统计学意义(P<0.05)。②治疗组的平均起效时间(3.00+2.04)d,对照组平均起效时间(7.00+1.58) d.,两组间差异有统计学意义(P<0.05)。结论巴氯芬用于治疗脑卒中后主观感觉异常疗效显著,无明显毒副作用。%Objective To observe the effects of baclofen on stroke patients with subjective paresthesia.Methods 40 cases of stroke patients with subjective paresthesia were randomly divided into two groups: control group(n =20) received routine treatment, treatment group( n = 20) received routing treatment and baclofen. The treatment lasted for 14d.Total effective rate and average effective time were checked.Results①The total effective rate of treatment group was higher than that of control group)95.00% vs. 45.00%, P< 0.05).② The average effective time of treatment group was lower than that of ontrol group(7.00+1.58d vs 3.00+2.04d, P<0.05).Conclusions Baclofen can improve the symptom of sroke patients with subjective paresthesia, and baclofen has no evident toxic effects.

  7. 毛细管电泳分离-激光诱导荧光检测巴氯芬和加巴喷丁%Determination of baclofen and gabapentin by capillary electrophoresis-laser-induced fluorescence method

    Institute of Scientific and Technical Information of China (English)

    曹丽伟; 李聪; 任东

    2011-01-01

    采用新合成的6-氧-(N-琥珀酰亚胺乙酸酯)-9-(2’-甲氧羰基)荧光素(SAMF)作为柱前衍生试剂,用甘氨酸做内标,毛细管电泳分离-激光诱导荧光检测血清中的巴氯芬(baclofen)和加巴喷丁(gabapentin).研究表明,在磷酸盐缓冲溶液(pH=8)介质中,25℃下15 min即可完成衍生反应.以pH =5的30 mmol/L的磷酸盐缓冲溶液作为电泳介质,衍生产物在16 min内达到电泳基线分离,检出限为4×10-10 mol/L.将新建立的方法用于血清中巴氯芬、加巴喷丁的分析测定,回收率为95.5% ~ 102.01%,结果令人满意.%A sensitive and efficient analysis method for determination of baclofen and gabapentin in human serum based on capillary electrophoresis with laser-induced fluorescence (LIF) has been established. 6-Oxy-( N-succinimidylacetate)- 9-(2'-Meth-oxycarbonyl) fluorescein (SAMF), a new synthesized fluorescence reagent, was used for pre-column derivatization of the "non-fluorescent drug in serum. Glycin was used as an internal standard. The best derivation condition was obtained in phosphate buffer (pH =8) at 25℃ for 15 min. Optimal separation and detection were obtained with an background electrolyte of 30 mmol/L phosphate buffer ( pH = 5 ) and LJF was excited at 473 nm. The detection limit of baclofen was 4 x 10-10 mol/L. This sensitive method was effectively used to determine baclofen and gabapentin in human serum with recoveries ranging from 95.5% to 102.01%.

  8. Effect of baclofen on analgesia in the rat with chronic neuropathic pain%Baclofen对慢性神经痛大鼠镇痛效果的影响

    Institute of Scientific and Technical Information of China (English)

    杜冬萍; 陈志峰; 徐惠芳

    2003-01-01

    目的研究GABAB受体激动剂baclofen对慢性神经痛大鼠痛阈的影响以及对脊髓c-fos表达的影响,探讨脊髓GABA能系统在神经痛调节中的可能机制.方法结扎大鼠左侧L5脊神经根建立慢性神经痛模型.SD大鼠24只随机等分成(1)假手术+baclofen组:大鼠背部假手术而未行神经根结扎,术后28至34 d每天腹腔注射baclofen 10 mg/kg两次;(2)假手术组:背部假手术后28至34 d每天腹腔注射0.9% NaCl 2 ml两次;(3)L5结扎+baclofen组:实施L5神经根结扎,术后28至34 d每天腹腔注射baclofen 10 mg/kg两次;(4)L5结扎组:实施L5神经根结扎,术后28至34 d每天腹腔注射0.9% NaCl 2 ml两次.术后1、3、7、10、14、21、28、35 d测大鼠双后肢光热刺激性痛阈.术后35 d处死大鼠取出腰段脊髓,冰冻切片,免疫组化法检测c-fos免疫阳性细胞.结果 (1)术后7~28d,左L5脊神经结扎大鼠较假手术大鼠痛阈明显降低(P0.05),双侧脊髓深层(Ⅲ-Ⅹ层)FLI细胞无显著差异(P>0.05);(2)术后35 d,使用baclofen的L5结扎大鼠的左后肢痛觉显著低于未使用baclofen的L5结扎大鼠(P<0.01),前者脊髓深层(Ⅲ-Ⅹ层)FLI细胞显著减少(P<0.01).结论大鼠慢性疼痛引起的FLI细胞在脊髓深层Ⅲ-Ⅹ层表达增多.baclofen可减轻慢性神经痛大鼠痛觉过敏,使神经损伤后双侧脊髓深层FLI细胞表达减少.

  9. Baclofen prevented the changes in c-Fos and brain-derived neutrophic factor expressions during mecamylamine-precipitated nicotine withdrawal in mice.

    Science.gov (United States)

    Varani, Andrés P; Moutinho Machado, Lirane; Balerio, Graciela N

    2014-11-01

    Previous studies from our laboratory showed that baclofen (BAC, GABAB receptor agonist) prevented the behavioral and neurochemical alterations of nicotine (NIC) withdrawal syndrome. To further investigate the mechanisms underlying these effects, we analyzed the c-Fos and brain-derived neutrophic factor (BDNF) expression during NIC withdrawal and its prevention with BAC. Swiss-Webster mice received NIC (2.5 mg/kg, sc) four times daily, for 7 days. On the 8th day, NIC-treated mice received the nicotinic antagonist mecamylamine (MEC; 2 mg/kg, i.p.) 1 h after the last dose of NIC. A second group of NIC-treated mice received BAC (2 mg/kg, i.p.) prior to MEC administration. Thirty minutes after MEC, mice were sacrificed and the immunohistochemistry assays (c-Fos and BDNF) were performed at different anatomical levels. c-Fos expression decreased in the dentate gyrus of the hippocampus (DG) and the bed nucleus of the stria terminalis (BST), and increased in the habenular (Hb), accumbens shell (AcbSh) nuclei during NIC withdrawal. BAC re-established the modified c-Fos expression only in the DG, BST and AcbSh during NIC withdrawal. Conversely, BDNF expression decreased in the CA1 and CA3 area of the hippocampus, the Hb, and caudate putamen (CPu) during NIC withdrawal. Finally, BAC restored the decreased BDNF expression during NIC withdrawal in the CA1, CA3, Hb, and CPu. The results suggest a relationship between BAC's preventive effect of the expression of NIC withdrawal signs, and its ability to restore the changes in c-Fos and BDNF expression, observed in specific brain areas of NIC-withdrawn mice.

  10. Leucocytopenia and remitten fever induced by baclofen in one patient%巴氯芬致驰张热合并白细胞减少1例

    Institute of Scientific and Technical Information of China (English)

    姜从玉; 胡永善; 李放

    2003-01-01

    @@ 巴氯芬(baclofen),其化学名:4-氨基-3-(4-氯苯基)-丁酸,商品名:力奥来素(Lioresal),是一类肌松药物,γ-氨基丁酸(GABA)受体激动剂[1,2].巴氯芬作用于脊髓后,由于其对GABA受体有较高的亲和力,能与之结合,从而产生抑制兴奋性氨基酸释放的作用,如天门冬氨酸、谷氨酸;抑制脊髓的单突触反射和多突触反射,从而缓解骨骼肌痉挛状态,使肌张力降低,改善肌肉的功能状态等作用[3,4].治疗开始时常出现日间镇静、嗜睡和恶心等中枢神经系统的不良反应,偶尔出现欣快、抑郁、感觉异常、肌痛、肌无力、共济失调、震颤、眼球震颤、调节紊乱、幻觉和恶梦等神经精神病学症状;偶有轻度的胃肠功能紊乱(便秘、腹泻);低血压、心功能降低;偶有或罕见排尿困难、尿频、遗尿;个别病例有视力障碍、味觉障碍、多汗、皮疹、肝功能损害[5,6].巴氯芬引起驰张热合并白细胞降低作者未见国内外文献报道.现遇见1例报道如下.

  11. 白脉软膏与巴氯芬治疗脑卒中患者肌痉挛的疗效比较%Comparison of the effects of Baimai ointment and baclofen in stroke patients with spasticity

    Institute of Scientific and Technical Information of China (English)

    李亮; 陶林花; 施明; 任芸; 尹汉逵; 王月丽; 孙燕; 林斯捷

    2016-01-01

    Objective To compare the effects of Baimai ointment and baclofen in stroke patients with spas-ticity.Methods 84 cases accompanied by limb spasticity in stroke patients by digital table were randomly divided into Baimai ointment group and baclofen group,42 cases in each group.The Baimai ointment group were treated with Baimai ointment on the spastic limbs,the baclofen group received oral baclofen tablets 30 -75mg/days for 2 weeks, 4 weeks,8 weeks.The curative effects of the two groups were compared before and after treatment.Results Before and after treatment in the two groups,the levels of spasticity,pain and activities of daily living (ADL)differences were statistically significant and Baimai ointment in the treatment of spasm.After 4 weeks and 8 weeks,the Ashworth score of the Baimai ointment group were (1.59 ±0.46)points,(0.89 ±0.56)points,and those of baclofen group were (1.75 ±0.64)points,(1.45 ±0.48)points,the differences were statistically significant(t values were 2.916, 3.367,all P <0.05).After 2 weeks,4 weeks and 8 weeks,the VAS score of the Baimai ointment group were (2.72 ± 0.54)points,(2.02 ±0.24)points,(1.24 ±0.12)points,and baclofen group were (3.56 ±0.44)points,(3.15 ± 0.48)points,(2.58 ±0.26)points,the differences were statistically significant(t values were 2.975,3.359,5.416, all P <0.05),activities of daily living (ADL)was higher than that of the baclofen group.After 8 weeks,the MBI score of the Baimai ointment group was (64.46 ±10.78)points,and baclofen group was (50.74 ±9.18)points,the difference was statistically significant between the two groups (t values was 3.562,P <0.05).Conclusion Baimai ointment has the better antispasmodic effect than baclofen in patients with stroke.%目的:比较白脉软膏与巴氯芬改善脑卒中患者肌痉挛的疗效。方法将84例伴有肢体痉挛的脑卒中患者按数字表法随机分为白脉软膏组和巴氯芬组,每组42例,白脉软膏组予痉挛肢体外用白脉软膏,巴

  12. Curative effect observation of subjective paresthesia of baclofen therapy for cerebral apoplexy%巴氯芬治疗脑卒中后主观感觉异常的疗效观察

    Institute of Scientific and Technical Information of China (English)

    马琳; 薛韬

    2016-01-01

    ABSTRACT:Objective to observe effect of subjective paresthesia of baclofen therapy for cerebral apoplexy.Methods choose cerebral apoplexy patients with subjective paresthesia hospitalized in our hospital, randomly divide them into treatment and control group, 20 cases in control group were treated with routine therapy, and 20 cases in treatment group with baclofen tablets based on routine treatment. after 14 days of treatment, observe total effective rate and average effective time of subjective paresthesia recovery of two groups after treatment.Results after treatment, 1. total effective rate of treatment group was 95%, that of control group was 45%, difference between two groups showed statistical significance(P<0.05).average effective time of treatment group was (3.00±2.04)d, that of control group was (7.00±1.58)d, difference between two groups showed statistical significance (P<0.05).Conclusion baclofen has significant effect in treatment of subjective paresthesia of baclofen therapy for cerebral apoplexy without obvious side effect, which is worthy of clinical application.%目的:观察巴氯芬治疗脑卒中后主观感觉异常的效果。方法选择我院住院的伴有主观感觉异常的脑卒中患者,随机分为治疗组及对照组,对照组20例,采用常规治疗,治疗组20例,采用常规治疗基础上加用巴氯芬片治疗。治疗共14天,观察两组间治疗后主观感觉异常恢复的总有效率及平均起效时间。结果治疗后,①治疗组的总有效率为95%,对照组总有效率45%,两组间比较差异有统计学意义(P<0.05)。②治疗组的平均起效时间(3.00±2.04)d,对照组平均起效时间(7.00±1.58)d.,两组间差异有统计学意义(P<0.05)。结论巴氯芬用于治疗脑卒中后主观感觉异常疗效显著,无明显毒副作用,值得临床应用。

  13. 左归丸和巴氯芬联用对脑瘫鼠运动认知的影响%Effect of combined application of Zuoguiwan and Baclofen on motor and cognition of rats with cerebral palsy

    Institute of Scientific and Technical Information of China (English)

    李玲; 焦银香; 张菡; 李静; 李红霞

    2015-01-01

    Objective To investigate the effect of the combined application of Zuoguiwan and Baclofen on motor coordination ability and cognitive function of newborn rats with cerebral palsy ( CP) and to study its possible mechanism.Methods SD rats were randomly divided into sham-operated group, CP model without treatment group, CP model with Zuoguiwan group, CP model with Baclofen group, and CP model with Zuoguiwan combined with Baclofen group.Neurobehavioral indexes were detected in each group before treatment, 7, 14, 21 and 28 day treatment, and 7 day after treatment, respectively.TNF-αand NOS in serum, and MDA and SOD in brain tissue of rats were measured in each group 7 day after treatment.Results Compared with CP model without treatment group, muscle tension reduced significantly and the time of going through the balance reduced in Baclofen group and Zuoguiwan combined with Baclofen group after having taken the drugs for 14 days (t value was 4.603, 5.590, 6.337 and 5.575, respectively, all P0.05).Conclusion Compared with single drug therapy, combined application of Zuoguiwan and Baclofen can improve motor more obviously, and it may improve the cognition function of rats by protecting neurocyte and repairing neuron.%目的:探讨左归丸和巴氯芬联用对新生脑瘫大鼠运动协调能力和认知能力的影响,并研究其可能的机制。方法随机将SD大鼠分为假手术组、脑瘫( CP)模型未给药组、CP模型左归丸组、CP模型巴氯芬组以及CP模型左归丸+巴氯芬联用组。分别于药物处理前,处理7、14、21、28天及治疗结束后7天时分别测定各组大鼠神经行为学指标,治疗结束后7天后测定血清中肿瘤坏死因子( TNF-α),一氧化氮合酶( NOS)和脑组织中丙二醛( MDA)、超氧化物歧化酶( SOD)的变化。结果巴氯芬治疗组和联用组在服药14天后与同期CP模型未给药组比较肌张力显著降低(t值分别为4.603、5.590,均P<0

  14. 巴氯芬及β-环糊精的包结物与牛血清白蛋白的相互作用研究%Interaction of baclofen or its complex of β-cyclodextrin with bovine serum albumin

    Institute of Scientific and Technical Information of China (English)

    刘宇飞; 孙小梅; 王献; 李步海

    2011-01-01

    Objective : The inclusion interaction of β - cyclodextrin and baclofen, and the interactions of bovine ser um albumin and baclofen or complex were investigated. Methods : The inclusion interaction of β - cyclodextrin and baclofen was studied by UV spectra and H1NMR. The stoichiometry ratio for the formation of the inclusion comple xes was determined by molar ratio method. The constants of baclofen and β - cyclodextrin at different temperatures were estimated according to the formula. The interactions of bovine serum albumin and baclofen or complex have been studied by fluorescence spectroscopy. Results :The result showed that the inclusion process was spontaneous, the hydrophobic force was main binding force of β - cyclodextrin inclusion complex; Both baclofen and complex could quench the fluorescence of bovine serum albumin. Conclusion : The stoichiometry ratio for the formation of the inclusion complexes is 1∶1. The hydrophobic force of baclofen alone and bovine serum albumin is mainly interaction force, and the electrostatic force of inclusion compond and bovine serum albumin is mainly interaction force , for the reason that baclofen is included by the β - cyclodextrin.%目的:研究巴氯芬及β-环糊精的包结作用和巴氯芬及β-环糊精包结物与牛血清白蛋白的相互作用.方法:用紫外可见分光光度法与核磁共振法研究了β-环糊精对巴氯芬的包结行为;用摩尔比法确定了包结物的化学计量比;用公式计算了不同温度下巴氯芬与β-环糊精的包结常数;用荧光光谱法研究了巴氯芬与包结物对牛血清白蛋白牛血清白蛋白的相互作用.结果:巴氯芬与β-环糊精的包结过程是自发的,主要驱动力为疏水作用力;巴氯芬及包结物都会对牛血清白蛋白产生静态猝灭.结论:巴氯芬与β-环糊精的包结比为1:1;巴氯芬与牛血清白蛋白的主要作用为疏水作用,而包结物与牛血清白蛋白主要为静电作用,这是由于β-

  15. 胶束电动色谱-激光诱导荧光检测法测定肌松弛药巴氯芬%Determination of baclofen using micellar electrokinetic chromatography with laser induced fluorescence detection

    Institute of Scientific and Technical Information of China (English)

    王宇飞; 杨甲甲; 蔡元丽; 林夏; 李晖

    2011-01-01

    A novel micellar electrokinetic chromatographic method with laser induced fluorescence detection after derivatization with 4-chloro-7-nitrobenzo-2-oxa-l ,3-diazole( NBD-C1) was developed for the determination of muscle relaxant drug baclofen ( BAL). After optimization, baseline separation of the derivatives of BAL and gabapentin (internal standard) was obtained within 7 min in a running buffer (pH 9. 75) composed of 15 mmol/L sodium borate, 20 mmol/L sodium dodecyl sulfate and 10% (v/v) acetonitrile. The separation voltage was 17. 5 kV. The column temperature was 25 ℃. The samples were injected by a pressure of 3. 45 kPa(0. 5 psi) for 3 s. The method has a linear range of 0. 025 - 25 mg/L for BAL with the correlation coefficient of 0. 999 9. The limit of detection ( LOD, S/N = 3) and the limit of quantification (LOQ, S/Af = 10) were 0.90 |xg/L and 6.25 μg/L, respectively. The developed method was used for the analysis of BAL pharmaceutical preparation and urine samples spiked with BAL standard. The ranges of recovery were 101. 6% - 107. 9% for BAL preparation and 107. 0% - 109. 6% for urine samples. This method can be applied to the quality assessment of baclofen drug products, and provide supplementary means for the drug metabolism research of baclofen.%以4-氯-7-硝基苯并-2-氧杂-1,3-二唑(NBD-CIl)为柱前衍生试剂,建立了胶束电动色谱-激光诱导荧光检测法测定肌松弛药巴氯芬( BAL)的新方法.经过实验条件的优化,采用15 mmol/L硼砂、20 mmol/L十二烷基硫酸钠、10%(v/v)乙腈、pH 9.75的缓冲体系,在分离电压为17.5 kV、柱温为25℃的条件下,压力进样3.45 kPa(0.5 psi)×3s,巴氯芬及其内标物的衍生产物在7 min内实现较好的基线分离,线性范围为0.025 ~25 mg/L,相关系数为0 999 9,检出限(S/N=3)和定量限(S/N=10)分别为0.90 μg/L和6.25 μg/L.该方法被应用于巴氯芬制剂及加入巴氯芬对照品的尿液样品分析,回收率范围分别为101.6%~107.9

  16. Clinical analysis of carbamazepine combined with baclofen treating trigeminal neuralgia%卡马西平联合巴氯芬治疗三叉神经痛的临床分析

    Institute of Scientific and Technical Information of China (English)

    程福璋

    2015-01-01

    Objective To explore the clinical effect of carbamazepine combined with baclofen treating trigeminal neu-ralgia. Methods 82 patients with trigeminal neuralgia meeting clinical diagnostic criteria and received in our hospital from February 2013 to February 2015 were selected as study object.Patients were divided into control group and treat-ment group by random number table method,and each group was 41 cases.Patients in control group were treated simply with carbamazepine,while patients in treatment group were given carbamazepine combined with baclofen.Disappear time of trigeminal neuralgia symptom,the total time of medicine treatment plan implement,treatment effect and incidence rate of adverse reaction and so on in patients between two groups was compared respectively. Results The disappear time of trigeminal neuralgia symptom and the total time of medicine treatment plan implement in treatment group [(7.32±1.08) d and (10.75±1.68) d] was obviously shorter than that of control group [(10.68±2.15) d and (14.79±2.53) d] respectively (P<0.05).The total effective rate in treatment group (90.3%) was obviously higher than that of control group (68.3%) (P<0.05).The incidence rate of adverse reaction in treatment group (2.4%) obviously lower than that of control group (17.1%) (P<0.05). Conclusion The clinical effect is very obvious by using carbamazepine combined with baclofen treat-ing trigeminal neuralgia.%目的:探讨卡马西平联合巴氯芬治疗三叉神经痛的临床效果。方法选择2013年2月~2015年2月我院收治的符合临床诊断标准的三叉神经痛患者82例作为研究对象,采取随机数字表法将其分成对照组和治疗组,每组41例。对照组患者给予单纯卡马西平治疗;治疗组患者给予卡马西平联合巴氯芬治疗。比较两组患者的三叉神经痛症状消失时间和用药治疗计划实施总时间、治疗效果、不良反应发生率等。结果治疗组患者的三

  17. Characterization of bicuculline/baclofen-insensitive (rho-like) gamma-aminobutyric acid receptors expressed in Xenopus oocytes. II. Pharmacology of gamma-aminobutyric acidA and gamma-aminobutyric acidB receptor agonists and antagonists.

    Science.gov (United States)

    Woodward, R M; Polenzani, L; Miledi, R

    1993-04-01

    Poly(A)+ RNA from mammalian retina expresses bicuculline/baclofen-insensitive gamma-aminobutyric acid (GABA) receptors in Xenopus oocytes with properties similar to those of homooligomeric GABA rho 1 receptors. The pharmacological profile of these rho-like receptors was extended by measuring sensitivities to various GABAA and GABAB receptor ligands. For direct comparison the same compounds were also assayed with GABAA receptors expressed by rat brain RNA. The potency sequence for heterocyclic GABA analogues at the GABA rho-like receptors was GABA (1.3) > muscimol (2.3) > isoguvacine (100) (approximate EC50 in parentheses; all EC50 and Kb values given in microM). Both muscimol and isoguvacine were partial agonists at the rho-like receptors. 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol (Kb congruent to 32), piperidine-4-sulfonic acid (Kb congruent to 85), and isonipecotic acid (Kb congruent to 1000) acted primarily as competitive antagonists, showing little or no activity as agonists. The sulfonic acid GABA analogue 3-aminopropanesulfonic acid was also a competitive antagonist (Kb congruent to 20). Conformationally restricted GABA analogues trans- and cis-4-aminocrotonic acid (TACA and CACA) were agonists at the rho-like receptors. TACA (EC50 congruent to 0.6) had twice the potency of GABA and was 125 times more potent than CACA (EC50 congruent to 75). Z-3-(Amidinothio)propenoic acid, an isothiouronium analogue of GABA, had little activity as an agonist but instead acted as a competitive antagonist (Kb congruent to 20). At concentrations of > 100 microM, bicuculline did have some weak competitive inhibitory effects on the GABA rho-like receptors (Kb congruent to 6000), but it was at least 5000 times more potent at GABAA receptors. Strychnine (Kb congruent to 70) and SR-95531 (Kb congruent to 35) also were competitive inhibitors of the rho-like receptors but were, respectively, 20 and 240 times more potent at GABAA receptors. The GABAB receptor ligands baclofen

  18. 毛细管电泳分离-激光诱导荧光检测血清中的巴氯芬%Detection of Baclofen in Serum by Capillary Electrophoresis-Laser Induced Fluorescence Method

    Institute of Scientific and Technical Information of China (English)

    曹丽伟; 胡杨

    2011-01-01

    首次将新合成的柱前衍生试剂6-氧-(N-琥珀酰亚胺乙酸酯)-9-(2′-甲氧羰基)荧光素(SAMF)用于巴氯芬(Baclofen)的衍生标记,并采用毛细管电泳分离-激光诱导荧光(CE-LIF)法分离检测衍生物.研究表明,在磷酸盐缓冲溶液(pH=7.5)介质中,30℃下10min即可完成衍生反应.反应物在pH 5.6,35mmol·L-1的磷酸盐缓冲溶液中12min内达到分离,检出限为6×10-10mol·L-1.本法用于血清中巴氯芬的分析测定,回收率为95.8%-101.0%.

  19. The influence of GABAB receptor expression in the spinal dorsal horn of rats by using baclofen in combination with morphine%巴氯芬与吗啡联合应用对脊髓背角GABAB受体表达的影响

    Institute of Scientific and Technical Information of China (English)

    单文燕; 陈艳平; 曹德权

    2012-01-01

    目的 探讨巴氯芬与吗啡联合应用对脊髓背角GABAB受体表达的影响.方法 成年雄性SD大鼠48只鞘内置管成功后,随机均分为四组,分别鞘内注射生理盐水10μl(NS组),吗啡10μg(M组),巴氯芬0.5μg(B组)和巴氯芬0.5μg+吗啡10 μg(BM组).每天9:00和16:00鞘内注射,在9:30行热水浴甩尾潜伏期(TFL)测定,连测3次,间隔5 min,取其均值,将第1天注药后的TFL均值作为基础值,以TFL恢复到基础值作为出现吗啡耐受的标准.第11天晨,取大鼠腰段脊髓行免疫组织化学染色观察脊髓背角GABAB受体的表达.结果 注药后第10天M组大鼠TFL恢复至基础值,出现吗啡耐受现象,B组和BM组未出现吗啡耐受现象(P<0.01).M组GABABR1及GABABR2表达明显低于其它三组(P<0.01).结论 巴氯芬与吗啡联合应用可以减轻吗啡对脊髓背角GABAB受体表达的下调作用.%Objective To investigate the effects of GABAB receptor expression in the spinal dorsal horn of rats by using baclofen in combination with morphine. Methods Healthy male SD rats were randomly divided into four groups after the success of intrathecal cathetemation (n=12). They included saline group(group NS): 0. 9% saline 10 /μ∣, morphine group(group M). morphine 10 figs baclofen group(group B): baclofen 0. 5 μg, baclofen-morphine group (group BM): baclofen 0. 5 μg +morphine 10 μg. Drugs were given by intrathecal injection on 9:00 am and 16:00 pm for 10 consecutive days. At 9:30 the tail-flick latency (TFL) in rats were measured continued 3 limes with an interval of 5 mm. The mean value of TFL measured on the first day were considered as the baseline, and the return to baseline level of TFL were regarded as the morphine tolerance standard. In the morning of the eleventh day, spinal lumbar enlargement of rats were removed and cut into frozen sections to test GABAB receptors expression by immunohistochemical staining. Results TFL of rats returned to baseline in group M after 10 days

  20. The effect of baclofen on spontaneous and evoked behavioural expression of experimental neuropathic chronic pain Efeito do baclofeno sobre a expressão comportamental espontânea e evocada da dor crônica neuropática experimental

    Directory of Open Access Journals (Sweden)

    TEREZINHA DE JESUS T. SANTOS

    1999-09-01

    Full Text Available Baclofen (beta-p-chlorophenyl-GABA has been used in humans to treat spasticity, as well as trigeminal neuralgia. Since GABA (gamma-aminobutyric acid has been implicated in inhibitory and analgesic effects in the nervous system, it was of interest to study the effect of baclofen in experimental neuropathic pain. With this purpose, experiments were carried out in 17 neuropathic rats with constrictive sciatic injury, as described by Bennet and Xie (1988, taking as pain parameters scratching behaviour and the latency to the thermal nociceptive stimulus. The results showed that baclofen induces, in a dose-dependent manner, significant decrease (p O baclofeno (beta-p-clorofenil-GABA é usado em seres humanos para tratar espasticidade, assim como neuralgia do trigêmeo. Como o GABA (ácido amino-gama-butírico tem sido implicado em efeitos inibitórios e analgésicos no sistema nervoso, tornou-se de interesse estudar o efeito do baclofeno em dor neuropática experimental. Com esse objetivo, foram realizados experimentos em 17 ratos neuropáticos com lesão constritiva do nervo ciático, como descrito por Bennet e Xie (1988, tomando como parâmetros de dor o comportamento de coçar-se (scratching e a latência ao estímulo térmico nociceptivo. Os resultados mostraram que o baclofeno induziu, de forma dose-dependente, diminuição significativa (p < 0,05 do comportamento de coçar-se e aumento significativo (p < 0,05 da latência ao estímulo térmico nociceptivo. A ausência de antagonismo pela naloxona sugere a não participação de mecanismo opióide-mediado nesse efeito analgésico do baclofeno em dor neuropática experimental.

  1. 氯苯氨丁酸抑制脊髓背角神经元谷氨酸量子释放的机制%Mechanism for baclofen inhibition on quantal glutamate release in spinal dorsal horn neurons

    Institute of Scientific and Technical Information of China (English)

    马红雨; 杨鲲

    2004-01-01

    目的研究GABAB受体特异性激动剂氯苯氨丁酸(baclofen)在脊髓背角神经元抑制谷氨酸量子释放的机制.方法在脊髓薄片标本上,采用全细胞电压钳法记录脊髓背角神经元谷氨酸能的微兴奋性突触后电流(miniature excitatory postsynaptic currents;mEPSCs),通过分析这些电流的变化来研究baclofen影响谷氨酸量子释放的机制.结果 baclofen抑制mEPSCs的发放频率,但对平均幅度无明显影响,表明baclofen抑制谷氨酸释放的作用部位在突触前.在无钙溶液或者K+通道阻滞剂4-AP存在的条件下,baclofen对mEPSCs发放频率的抑制作用不受影响,但腺苷酸环化酶激动剂foskolin (可使cAMP保持在较高水平)能降低其抑制作用.而蛋白激酶C (PKC)激动剂PDBu对baclofen的抑制作用无影响.用NEM破坏G蛋白,则可取消baclofen的抑制效果.结论 baclofen不是通过影响突触前Ca2+通道或K+通道,或PKC途径,而是通过作用于G蛋白和(或)cAMP途径抑制谷氨酸的释放;这种抑制作用可能参与baclofen在脊髓水平的镇痛.

  2. 巴氯酚并康复训练对脑卒中患者痉挛性偏瘫的治疗效应%Efficacy of baclofen combined with rehabilitation training in stroke patients with spastic hemiplegia

    Institute of Scientific and Technical Information of China (English)

    姚金荣; 王东生; 倪新宝; 戎黛敏; 郑惠民

    2004-01-01

    目的:观察巴氯酚(Baclofen)结合康复治疗对脑卒中痉挛性偏瘫患者关节活动度、运动功能和ADL等方面的影响.方法:对144.例脑卒中痉挛性偏瘫患者,随机分为治疗组和对照组.治疗组84例,服用巴氯酚结合康复治疗;对照组60例,只接受康复治疗.在治疗前和治疗后12周分别进行Ashworth,FMA和MBI量表评定以观察疗效.结果:治疗后Ashworth评定治疗组显效率为67.86%(上肢),63.60%(下肢),有效率为86.90%(上肢),89.29%(下肢);对照组显效率为41.60%(上肢),45.00%(下肢),有效率为76.67%(上肢),78.33%(下肢).两组患者关节活动度、运动功能和生活能力均有明显改善(P<0.01),但治疗组明显优于对照组(P<0.05).结论:巴氯酚结合康复治疗能明显改善脑卒中偏瘫肢体的痉挛状态,提高患者的关节活动度、运动功能和生活能力.

  3. Baclofen for Treating Children with Refractory Gastroesophageal Reflux Induced Cough in 40 Cases%巴氯芬治疗儿童难治性胃食管反流性咳嗽40例临床评价

    Institute of Scientific and Technical Information of China (English)

    黄静; 吴绍英

    2015-01-01

    目的:观察巴氯芬用于儿童难治性胃食管反流性咳嗽治疗的临床疗效及安全性。方法选择2014年收治的难治性胃食管反流性咳嗽患儿80例,随机分为观察组与对照组,各40例。两组均指导调节生活方式,对照组予多潘立酮片(每次0.3 mg/kg,3次/日),奥美拉唑镁肠溶片(每次20 mg,1次/日)。观察组在对照组的基础上加用巴氯芬片(每次0.25 mg/kg,4次/日)。两组患儿疗程均为8周。观察并记录患儿治疗期间咳嗽、反酸、胸骨后灼热感以及嗳气等临床症状的变化,并对治疗前后临床症状的严重程度、症状发生频率进行评分。观察患者治疗前后。记录治疗前后患者血常规、肝肾功能及不良反应。结果治疗后,观察组临床疗效总有效率为92.50%,明显高于对照组的67.50%( P <0.05)。与治疗前比较,两组患儿治疗后各项症状积分及症状总积分均有减少( P<0.05),且观察组减少程度更加明显( P<0.05)。观察组的不良反应发生率为22.50%,明显高于对照组的7.50%( P<0.05),均能耐受,不影响后续治疗。两组患儿用药前后血常规、肝肾功能均未见明显变化。结论巴氯芬可有效治疗儿童难治性胃食管反流性咳嗽,虽然存在一定程度的嗜睡、乏力等不良反应,但能明显改善患儿的临床症状,可对抑酸治疗不能完全缓解症状的患儿进行辅助治疗。%Objective To observe the clinical effect and safety of baclofen for treating children with refractory gastroesoPhageal reflux in-duced cough. Methods 80 cases of refractory gastroesoPhageal reflux induced cough in the hosPital were randomly selected and divided into the observation grouP and the control grouP,40 cases in each grouP. Both grouPs were guided to adjust the way of life. The control grouP was treated with DomPeridone Tablets [ 0. 3 mg/ ( kg · time ) ,3 times/d ] ,Ome

  4. Inhibitory Effect of Baclofen on GABA-and NMDA-Activated Currents in Neurons Freshly Dissociated from Rat Dorsal Root Ganglion%Baclofen对大鼠新鲜分离DRG神经元GABA和NMDA激活电流的抑制作用

    Institute of Scientific and Technical Information of China (English)

    赵义梅; 木拉提; 王英姿; 呼海燕; 司军强

    2002-01-01

    用全细胞膜片箝技术在大鼠新鲜分离的背根神经节(DRG)细胞上观察到baclofen对GABA和NMDA激活电流有调制作用.单独给予DRG细胞baclofen (1~100 μmol/L)未记录到可测的电流改变,但预加baclofen 对GABA和NMDA激活电流具有明显的抑制作用,且呈剂量依赖性.100 μmol/L baclofen对GABA和NMDA激活电流分别抑制(51.2±10.9)%(X±SE,n=8,P<0.01)和(64.1±21.1)%(X±SE,n=6,P<0.01),此抑制作用是可逆的,可被GABAB受体拮抗剂saclofen(100 μmol/L )所取消(n=4).

  5. 鞘内注射巴氯酚对神经病理性痛大鼠的镇痛作用及其对脊髓GABA转运体-1的影响%Effects of intrathecal injection of GABAB receptor agonist baclofen on hyperalgesia and spinal GAT-1 of neuropathic rats

    Institute of Scientific and Technical Information of China (English)

    朱珊珊; 谭珊珊; 曾因明

    2011-01-01

    目的 研究鞘内注射GABAB受体激动剂巴氯酚(baclofen,Bac)对神经病理性痛大鼠的镇痛作用及其对脊髓GABA转运体-1的影响.方法 建立坐骨神经结扎致神经病理性痛大鼠模型.在行为学实验部分,将32只大鼠随机分为NS组、Bac1组、Bac2组、Bac3组(n=8),分别鞘内注射生理盐水、0.1、0.3、1.0 μg巴氯酚10 μl,并分别于给药前、给药后0.5、1、2、4、8、12、24 h测定大鼠机械缩足反射阈值(mechanical withdrawl threshold,MWT)和热缩足反射潜伏期(thermal withdrawl latency,TWL)以及运动功能.在第2部分,将大鼠分为 NS组与Bac组,鞘内分别给予0.3 μg巴氯酚或生理盐水,分别于给药前、给药后1、4、8 h取大鼠脊髓腰段,免疫组织化学检测脊髓节段GAT-1免疫阳性神经元(n=6);分别于给药前、给药后30 min、1、2、4、8、12和24 h取大鼠脊髓腰段,用Western blot方法测定脊髓节段GAT-1蛋白含量(n=4).结果 鞘内注射巴氯酚后0.5~2 h,Bac1组、Bac2组与Bac3组大鼠MWT和TWL均较NS组明显升高(P0.05).结论 鞘内注射GABAB受体激动剂巴氯酚可减轻坐骨神经结扎致神经病理性痛大鼠的痛觉过敏,其镇痛作用可能与抑制脊髓水平GAT-1的表达有关.%Aim To explore the effects of intrathecal injection of GABAB receptor agonist baclofen on hyperalgesia and spinal GAT-I of neuropathic rats induced by chronic constriction of sciatic nerve. Methods The left common sciatic nerve of anesthetized rats was tied loosely to establish the chronic constriction injury CCI ) model. For the behavioral experiments, 32 rats exhibiting neuropathic pain after nerve ligation were divided into 4 groups ( n =8 ): NS group, Bacl group,Bac2 group and Bac3 group, which were intrathecally injected with normal saline, 0. 1 . 0. 3 and 1. 0 μg baclofen respectively. MWT ( mechanical withdrawl threshold )and TWL( thermal withdrawl latency ) were recorded before drug administration, 0. 5 . 1, 2. 4, 8,12 h

  6. 联合应用巴氯芬、埃索美拉唑和莫沙必利治疗难治性胃食管反流病的疗效%Efficacy of Baclofen Combined with Esomeprazole and Mosapride on Refractory Gastroesophageal Reflux Disease

    Institute of Scientific and Technical Information of China (English)

    吴登峰; 黄中华; 陈思杰

    2014-01-01

    背景:对常规剂量质子泵抑制剂治疗无反应的胃食管反流病( GERD)称为难治性胃食管反流病( rGERD),国内主要联合多种药物治疗rGERD患者,但巴氯芬的报道较少见。目的:探讨巴氯芬联合埃索美拉唑和莫沙必利治疗rGERD的疗效。方法:纳入2013年3月-2014年4月福建省莆田市第一医院72例rGERD患者,随机分为两组。A组患者口服埃索美拉唑20 mg bid +莫沙必利5 mg tid +巴氯芬5 mg tid;B组口服埃索美拉唑20 mg bid +莫沙必利5 mg tid,疗程均为8周。比较两组症状、内镜下食管炎改善情况和不良反应。结果:治疗8周后,两组烧心、反酸、胸骨后疼痛、吞咽困难、症状总计分均较治疗前显著降低( P﹤0.05),A组症状改善总有效率显著高于 B组(90.6%对70.0%;χ2=4.585,P=0.032)。两组内镜下食管炎分级情况明显改善,A组内镜下治疗有效率显著高于B组(93.8%对75.0%;χ2=4.500,P=0.034)。巴氯芬的主要不良反应为嗜睡、头晕和乏力,患者均能耐受。结论:巴氯芬联合埃索美拉唑和莫沙必利是一种有效治疗rGERD的方法。%Background:Gastroesophageal reflux disease( GERD)that does not respond satisfactorily to standard proton pump inhibitor is defined as refractory gastroesophageal reflux disease( rGERD). Combined therapy is used to treat rGERD, however,the addition of baclofen is rarely studied. Aims:To investigate the efficacy of baclofen combined with esomeprazole and mosapride on rGERD. Methods:Seventy-two patients with rGERD from March 2013 to April 2014 at the First Hospital of Putian City were enrolled and randomly divided into group A and group B. Patients in group A were orally administrated with esomeprazole 20 mg bid + mosapride 5 mg tid + baclofen 5 mg tid. Patients in group B were treated with esomeprazole 20 mg bid + mosapride 5 mg tid. The treatment course was 8 weeks. The efficacy on symptoms, esophagitis

  7. Biocatalytic desymmetric hydrolysis of 3-(4-chlorophenyl)-glutaronitrile to the key precursor of optically pure baclofen%生物催化3-(4-氯苯基)-戊二腈去对称性水解合成光学纯巴氯芬的关键前体

    Institute of Scientific and Technical Information of China (English)

    徐美珍; 任杰; 龚劲松; 董文玥; 吴洽庆; 许正宏; 朱敦明

    2013-01-01

    研究了利用生物催化剂制备(S)-4-氰基-3-(4-氯苯基)-丁酸.以3-(4-氯苯基)-戊二腈为底物,采用苯酚-次氯酸钠法对实验室保藏的菌株进行筛选,得到一株产物立体选择性较高的菌株赤霉菌Gibberella intermedia WX12,并对其催化特性和发酵条件进行了初步研究.以30 g/L的乳糖和20 g/L的蛋白胨分别为碳、氮源,发酵培养96 h,收集的菌体在50 mmol/L磷酸缓冲液(pH 8.0)中30℃催化反应24 h,将3-(4-氯苯基)-戊二腈转化为4-氰基-3-(4-氯苯基)-丁酸,产率为90%.将产物化学转化为巴氯芬,手性HPLC分析表明水解产物构型是(S),其对映异构体过量值ee> 99%.该产物可以用来合成光学纯的(R)-和(S)-巴氯芬.%We produced (S)-4-cyano-3-(4-chlorophenyl)-butyrate by highly stereoselective biocatalyst in this study. A nitrilase-producing strain, named Gibberella intermedia WX12, was isolated by 3-(4-chlorophenyl)-glutaronitrile as substrate in the screening with phenol-sodium hypochlorite method. The fermentation conditions and catalytic properties of this strain were investigated. The preferred carbon and nitrogen sources for nitrilase production were lactose (30 g/L) and peptone (20 g/L). After being cultivated for 96 h, the cells were collected for use in biotransformation. The hydrolysis of 3-(4-chlorophenyl)-glutaronitrile was performed at 30 ℃ in phosphate buffer (pH 8.0, 50 mmol/L) for 24 h to give (S)-4-cyano-3-(4-chlorophenyl)-butyric acid with 90% yield and >99% of ee, which can be used for the synthesis of (R)-and (S)-baclofen. The configuration of product was determined by chemically converting it to baclofen and comparison with the authentic sample by chiral HPLC analysis.

  8. Effect of diabetes on baclofen-induced inhibition of mEPSCs in spinal glutamatergic neurons in rats with neuropathic pain%糖尿病因素对巴氯芬抑制神经痛大鼠脊髓谷氨酸能神经元突触后电流的影响

    Institute of Scientific and Technical Information of China (English)

    白惠萍; 彭云水; 王倩; 吴川; 刘飞飞; 刘朋; 郭跃先; 王秀丽

    2014-01-01

    Objective To evaluate the effect of diabetes on baclofen-induced inhibition of miniature excitatory postsynaptic currents (mEPSCs) in spinal glutamatergic neurons in rats with neuropathic pain.Methods Thirty male Sprague-Dawley rats,aged 4 weeks,weighing 150-170 g,were randomly divided into 2 groups (n=15 each group):control group (C group) and diabetic neuropathic pain group (D group).Diabetic neuropathic pain was induced by intraperitoneal injection of streptozotocin 50 mg/kg and confirmed 28 days later by blood glucose > 16.7 mmol/L and pain threshold < 4 g in group D,while the rats received the equal volume of normal saline in C group.The animals were anesthetized with intraperitoneal 10% chloral hydrate 50 mg/kg.The rats were then sacrificed and lumbar segments (L1.5) of the spinal cord were removed for slice preparations.Glutamatergic mEPSCs in lamina Ⅱ neurons were recorded by using whole-cell patch-clamp technique and 20 neurons located in lamina Ⅱ of the spinal cord were recorded in each group.The cells stabilized for 30 min after sealing,and then baclofen with the final concentrations of 1,10,20,50 μmol/L was added to the perfusion solution at 5 min intervals followed by washout.The frequency and intensity of glutamatergic mEPSCs were recorded immediately before and after administration and at 5 min after washout.The inhibitory effect of baclofen on glutamatergic mEPSCs was measured and the inhibitory rate was calculated.Results Compared with group C,the frequency of glutamatergic mEPSCs was significantly increased and the inhibitory rate was decreased under each concentration (P < 0.05),and no significant change was found in the intensity of mEPSCs under each concentration in D group (P > 0.05).Conclusion Diabetes decreases baclofen-induced analgesic effect in rats with neuropathic pain,which is related to inhibition of mEPSCs in spinal glutamatergic neurons.%目的 评价糖尿病因素对巴氯芬抑制神经痛大鼠脊髓谷氨酸

  9. The intervention effect of rectal administration of Baclofen combined with comprehensive rehabilitation on the spastic state in the recovery period of stroke%巴氯酚直肠给药配合综合康复对脑卒中恢复期偏瘫痉挛状态的干预效应

    Institute of Scientific and Technical Information of China (English)

    杨贵青

    2012-01-01

    Objective To explore more effective ways to improve hemiplegia spasticity of stroke in the recovery period. Methods 100 subjects were given Baclofen rectal administration (retention enema) + comprehensive rehabilitation measures in the treatment of muscle spasticity on the basis of the implementation of the conventional treatment of neurology and stable conditions and physical signs. The dose was once 15 mg in the first day, then with an increase of 5-10 mg per day, the enema of 14 d was a course of treatment, for three courses. The comprehensive rehabilitation measures included good limb placed to maintain joint mobility, ease of body movement to control the static stretch around the cramps, muscle spasms, passive movement and massage. The effects were evaluated before treatment and after treatment of 32 d. Results 32 d after treatment compared with before treatment, the patient's muscle tone to improve the situation had a significant difference (P < 0.01). Muscle tone after treatment showed significant improvement, and gradually returned to normal; the results of the ADL score also had a significant difference (P < 0.01), and prompt patients after treatment of 32 d, the activities of daily living improved significantly. Conclusion Rectal administration of Baclofen with comprehensive rehabilitation training is helpful for the neurological rehabilitation of stroke patients and can improve the prognosis of stroke patients with hemiplegia spasm.%目的 探讨改善脑卒中恢复期偏瘫痉挛状态更为有效的方法.方法 100例研究对象在实施神经内科常规治疗以及病情和生命体征稳定的情况下,采用巴氯酚直肠给药(即保留灌肠)+综合康复措施治疗肌痉挛状态.用药第1天剂量为15 mg/次,然后每天增加5~10 mg,灌肠14 d为1个疗程,连续治疗3个疗程.综合康复措施具体内容包括良肢位的摆放、保持关节的活动度、缓解身体运动控制点周围痉挛、肌肉痉挛的静态牵拉、

  10. INHIBITORY EFFECT OF BACLOFEN ON GABA-ACTIVATED CURRENT IN MECHANICALLY ISOLATED PYRAMIDAL CELLS OF RAT HIPPOCAMPUS%Baclofen对机械分离的大鼠海马锥体细胞GABA-激活电流的抑制作用

    Institute of Scientific and Technical Information of China (English)

    甘志强; 罗加烈; 郑少萍; 李之望

    2004-01-01

    在机械分离的海马锥体细胞上,应用全细胞膜片钳技术.证明大多数细胞(88.5%,46/52)对GABA敏感.10-5~10-3mol/L的GABA引起一剂量依赖性、有明显去敏感作用的内向电流.预加3×10-5 mol/L baclofen(GABAB受体的特异性激动剂)30 s后再加GABA,84.8%(39/46)的细胞GABA-激活电流被抑制,其中仅有一个细胞(2.2%,1/46)GABA-激活电流幅值增强,13%(6/46)的细胞GABA-激活电流幅值无变化.预加baclofen后,GABA-激活电流量-效曲线明显下移.预加baclofen前后IGABA量效曲线的Kd值非常接近(1.0X10-4 vs1.4×10-4mol/L).经saclofen预处理可消除baclofen对GABA-激活电流的抑制.这与我室以往在外周神经元上的研究结果一致.本文结果不仅证明了GABAA和GABAB受体在海马锥体细胞上的共存,而且也证明了GABAB受体激活后对GABAA受体功能抑制这一现象无论在外周或中枢神经系统均具有普遍性.

  11. Effect of intrathecal baclofen on excitatory amino acids in spinal cords of acute pain rat model%鞘内注射巴氯芬对急性切口痛大鼠脊髓兴奋性氨基酸含量的影响

    Institute of Scientific and Technical Information of China (English)

    杜冬萍; 徐永明; 江伟

    2007-01-01

    目的 研究急性疼痛时脊髓内兴奋性氨基酸含量的变化、γ-氨基丁酸B受体(GABAB受体)激动剂巴氯芬(baclofen)的镇痛作用及其与脊髓兴奋性氨基酸含量变化的关系.方法 SD大鼠鞘内置管后行左后爪足底切口建立急性切口痛大鼠模型,随即分为假手术组、0.9%氯化钠溶液组、1μ巴氯芬组(鞘内注射巴氯芬1μg)和5μg巴氯芬组(鞘内注射巴氯芬5μg),每组25只.观察大鼠左后爪机械痛阈,并于术后1、2、6、12、24 h分离大鼠腰膨大部脊髓节段,检测其中兴奋性氨基酸的含量.结果 所有手术组的痛阈均明显低于假手术组(P值均<0.05),脊髓兴奋性氨基酸含量明显增加(P值均<0.05).鞘内注射巴氯芬后3 h内可以部分提高大鼠的痛阈(P值均<0.05),且鞘内注射5μg巴氯芬较1μg后3 h内大鼠的痛阈明显提高(P值均<0.05).鞘内注射1或5μg巴氯芬大鼠脊髓兴奋性氨基酸含量较使用0.9%氯化钠溶液大鼠明显下降(P值均<0.05).结论 大鼠脚爪切口痛模型可以引起大鼠局部痛阈降低,脊髓兴奋性氨基酸含量提高.鞘内注射巴氯芬可以提高切口痛大鼠的局部痛阈,并且抑制脊髓兴奋性氨基酸的升高.

  12. Baclofen as relapse prevention in the treatment of gamma-hydroxybutyrate dependence: a case series

    NARCIS (Netherlands)

    Kamal, R.M.; Loonen, A.J.; Dijkstra, B.A.; Jong, C.A.J. de

    2015-01-01

    In the last decade, gamma-hydroxybutyrate (GHB) abuse and dependence have increased. It has been reported that GHB dependence has a high rate of relapse, serious complications of intoxication, and a potentially life-threatening withdrawal syndrome. Nevertheless, in clinical practice, there is no kno

  13. Baclofen for intractable hiccup%巴氯芬治疗顽固性呃逆

    Institute of Scientific and Technical Information of China (English)

    陈协辉; 吴贤仁

    2001-01-01

    目的:观察巴氯芬对顽固性呃逆的疗效.方法:80例顽固性呃逆病人分为2组,其中治疗组42例(男性28例,女性14例,年龄48 a±s 8 a)采用巴氯芬治疗.最小剂量是10 mg,bid.最大剂量为15 mg,tid.小剂量开始,逐步递增.疗程4 d.38例对照组(男性24例,女性14例,年龄44 a±11 a)采用氯丙嗪、苯妥英、硝苯地平、东莨菪碱等常规治疗.结果:治疗组总有效率98 %,对照组总有效率58 %(P<0.05),治疗组服药d 1起效率86 %,对照组服药d 1起效率21 %(P<0.01),治疗组疗程明显缩短(P<0.01),不良反应少.结论:巴氯芬是治疗顽固性呃逆较为有效的药物.

  14. 不对称氢转移合成R-(-)-Baclofen

    Institute of Scientific and Technical Information of China (English)

    许波洪; 张跃

    2010-01-01

    以外消旋的β-羟基酮酸酯为原料,通过不对称氢转移的方法,高效的合成了光学活性的手性中间体β-羟基酮酸酯,光学纯度达到98%,然后通过亲核取代反应生成了光学活性的β-氰基丙酮酸酯,最后还原生成R-(-)-Baclofen。

  15. New Technical Synthesis of(R)-Baclofen%(R)-巴氯芬的合成研究

    Institute of Scientific and Technical Information of China (English)

    陈云华; 毛侦军; 杨伟强; 林旭锋

    2008-01-01

    从对氯苯乙酮出发,经过Wittig-Homer、溴代、酞酰亚胺化、不对称还原和酸解反应五步合成了(R)-巴氯芬,总收率达到了62%.目标产物的结构经过核磁和质谱的确证.

  16. Baclofen as relapse prevention in the treatment of Gamma- Hydroxybutyrate (GHB) dependence: an open label study

    NARCIS (Netherlands)

    Kamal, R.M.; Schellekens, A.F.A.; Jong, C.A.J. de; Dijkstra, B.A.

    2015-01-01

    BACKGROUND: GHB dependence is a growing health problem in several western countries, especially the Netherlands. Attempts to stop using GHB are often followed by relapse shortly after successful detoxification. Craving for GHB use and co-morbid psychiatric symptom levels are thought to be the major

  17. [Double blind placebo controlled randomized pilot clinical trial of baclofen (Baclosan®) for alcohol dependence].

    Science.gov (United States)

    Krupitsky, E M; Rybakova, K V; Kiselev, A S; Alexeeva, Yu V; Berntsev, V A; Chekhlaty, E I; Zubova, E Yu; Popov, Yu V; Neznanov, N G

    2015-01-01

    Цель исследования — изучение эффективности применения баклофена (препарат «баклосан») для стабилизации ремиссии у больных алкоголизмом. Материал и методы. Обследовали 32 больных алкоголизмом, которые случайным образом распределялись в одну из двух групп. Больным 1-й группы (16 человек) был назначен баклофен (50 мг/сут) в течение 3 месяцев; больные 2-й группы получали идентично выглядящее плацебо. Все больные еженедельно должны были посещать клинику для контроля ремиссии (потребления алкоголя), оценки выраженности влечения к алкоголю (крэйвинга), аффективных расстройств (депрессии и тревоги), активности гамма–глутамилтранспептидазы (ГГТ) и комплайенса приема препаратов (по рибофлавину в моче). Для контроля потребления алкоголя применяли методику ретроспективного анализа и определение активности ГГТ. Для оценки тревоги использовали шкалы Гамильтона и Спилбергера. Для оценки депрессии — шкалу Монтгомери-Ашберг. Влечение к алкоголю оценивали с помощью обсессивно-компульсивной, пенсильванской и визуальной аналоговой шкал. Для общей оценки эффективности терапии использовали шкалу общего клинического впечатления. Исследование проводилось двойным слепым методом. Результаты и заключение. Установлено, что баклофен статистически значимо не отличается от плацебо по показателям эффективности стабилизации ремиссии у больных алкоголизмом (вероятно, это обусловлено недостаточным объёмом выборки). Показатели удержания больных в ремиссии и потребления алкоголя в группе баклофена были несколько лучше, чем в группе плацебо, а различия между группами по данным показателям приближались к уровню статистической значимости, что позволяет говорить о выявленной тенденции к большей эффективности баклофена при алкоголизме по сравнению с плацебо. Баклофен достоверно не отличался от плацебо по количеству побочных эффектов (нежелательных явлений) и влиянию на активность ферментов печени, что свидетельствует о его хорошей переносимости и безопасности применения у данного контингента больных. Авторы считают, что для обоснованного заключения об эффективности применения баклофена для лечения алкоголизма необходимы дальнейшие исследования на больших по размеру выборках больных.

  18. 盐酸巴氯芬的合成%Synthesis of Baclofen Hydrochloride

    Institute of Scientific and Technical Information of China (English)

    江淼; 谌志华; 邹志芹; 马红梅; 虞心红

    2010-01-01

    对氯苯甲醛和丙二酸经Knoevenagel-Doebner反应、硫酸氢钾催化下酯化得到3-(4-氯苯基)丙烯酸甲酯,再经Michael加成、水解、催化氢化及成盐制得解痉药盐酸巴氯芬,总收率约52%.

  19. Medicines to Treat Muscle Spasms and Pain

    Science.gov (United States)

    ... Reports recommends methocarbamoI or chlorzoxazone . For muscle spasticity :  Baclofen If baclofen does not work well for you, then Consumer Reports recommends tizanidine . Cyclobenzaprine and baclofen are both prescription medicines. Cyclobenzaprine costs $8 to $ ...

  20. Gait or Walking Problems

    Science.gov (United States)

    ... for stretching and exercising, and appropriate assistive devices. Baclofen and tizanidine are the medications most often used ... treatments such as botulinum toxin (Botox) and intrathecal baclofen (baclofen pump) can be helpful in some patients. ...

  1. Baclofen and other GABAB receptor agents are allosteric modulators of the CXCL12 chemokine receptor CXCR4.

    Science.gov (United States)

    Guyon, Alice; Kussrow, Amanda; Olmsted, Ian Roys; Sandoz, Guillaume; Bornhop, Darryl J; Nahon, Jean-Louis

    2013-07-10

    CXCR4, a receptor for the chemokine CXCL12 (stromal-cell derived factor-1α), is a G-protein-coupled receptor (GPCR), expressed in the immune and CNS and integrally involved in various neurological disorders. The GABAB receptor is also a GPCR that mediates metabotropic action of the inhibitory neurotransmitter GABA and is located on neurons and immune cells as well. Using diverse approaches, we report novel interaction between GABAB receptor agents and CXCR4 and demonstrate allosteric binding of these agents to CXCR4. First, both GABAB antagonists and agonists block CXCL12-elicited chemotaxis in human breast cancer cells. Second, a GABAB antagonist blocks the potentiation by CXCL12 of high-threshold Ca(2+) channels in rat neurons. Third, electrophysiology in Xenopus oocytes and human embryonic kidney cell line 293 cells in which we coexpressed rat CXCR4 and the G-protein inward rectifier K(+) (GIRK) channel showed that GABAB antagonist and agonist modified CXCL12-evoked activation of GIRK channels. To investigate whether GABAB ligands bind to CXCR4, we expressed this receptor in heterologous systems lacking GABAB receptors and performed competition binding experiments. Our fluorescent resonance energy transfer experiments suggest that GABAB ligands do not bind CXCR4 at the CXCL12 binding pocket suggesting allosteric modulation, in accordance with our electrophysiology experiments. Finally, using backscattering interferometry and lipoparticles containing only the CXCR4 receptor, we quantified the binding affinity for the GABAB ligands, confirming a direct interaction with the CXCR4 receptor. The effect of GABAergic agents on CXCR4 suggests new therapeutic potentials for neurological and immune diseases.

  2. Baclofen-Amitriptyline Hydrochloride-Ketamine Gel in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer

    Science.gov (United States)

    2015-07-03

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neurotoxicity; Pain; Unspecified Adult Solid Tumor, Protocol Specific

  3. An algorithmic approach to the management of unrecognized hydrocephalus in pediatric candidates for intrathecal baclofen pump implantation

    Directory of Open Access Journals (Sweden)

    Brian W Hanak

    2016-01-01

    Conclusions: Given the potentially high rate of elevated ICP and arrested hydrocephalus, the authors advocate pre-implantation assessment of ICP under controlled conditions and a thoughtful consideration of the neurosurgical management options for patients with elevated ICP.

  4. 脊舒治疗顽固性呃逆40例%Baclofen Treating 40 Cases of Refractory Hiccup

    Institute of Scientific and Technical Information of China (English)

    毛志光

    2002-01-01

    脊舒治疗顽固性呃逆病人62例,治疗组40例,用脊舒10mg,bid,po.对照组22例,用苯妥英钠0.1,tid,po,胃复安10mg,tid,po,加两侧足三里穴位封闭.结果治疗组总有效率97.5%,对照组总有效率59.1%(P<0.01),两组疗效有非常显著差异.

  5. Baclofen as relapse prevention in the treatment of Gamma- Hydroxybutyrate (GHB) dependence: an open label study [Study protocol

    NARCIS (Netherlands)

    Kamal, R.M.; Schellekens, A.F.A.; Jong, C.A.J. de; Dijkstra, B.A.G.

    2015-01-01

    Background GHB dependence is a growing health problem in several western countries, especially the Netherlands. Attempts to stop using GHB are often followed by relapse shortly after successful detoxification. Craving for GHB use and co-morbid psychiatric symptom levels are thought to be the major f

  6. Analysis of Baclofen by HPLC%巴氯酚的高效液相色谱分析方法

    Institute of Scientific and Technical Information of China (English)

    黄朋勉; 陈巨涛; 吴莹; 徐果果; 唐文娟

    2014-01-01

    建立了简便、快捷巴氯酚[4-氨基-3-(4-氯苯基)-丁酸]的高效液相色谱定量分析方法;色谱柱Diamonsil C18 column (250 mm×4.6 mm),流动相v(0.30 mol/L冰醋酸水溶液)∶v(甲醇)∶v(0.36 mol/L乙酸钠水溶液)=55∶44∶20,流速1.0 mL/min,检测波长226 nm.方法精密度良好,RSD值为0.11%(n=5),平均加标回收率为100.54%,RSD为1.76%(n=5).

  7. SCI with Brain Injury: Bedside to Bench Modeling for Developing Treatment and Rehabilitation Strategies

    Science.gov (United States)

    2013-10-01

    DEXTROSE 1 MICONAZOLE 2 MICONAZOLE 1 HEPARIN 1 HEPARIN 3 FENTANYL 1 FENTANYL 2 BACLOFEN 1 BACLOFEN 1 FERROUS SULFATE 1 FERROUS SULFATE 1 QUETIAPINE 1...TRAZODONE 3 TRAZADONE 5 BACLOFEN 3 BACLOFEN 3 OXYCODONE 3 OXYCODONE 2 LACTOBACILLUS 3 LACTOBACILLUS 1 MICONAZOLE 3 MICONAZOLE 1 FERROUS GLUCONATE 2 FERROUS...prescribed, together with mild analgesics and antacids, but albuterol and low molecular weight heparin have been discontinued and the use of baclofen

  8. Effects of the GABAB Receptor-Positive Modulators CGP7930 and rac-BHFF in Baclofen- and γ-Hydroxybutyrate-Discriminating Pigeons

    OpenAIRE

    Koek, Wouter; France, Charles P.; Cheng, Kejun; Rice, Kenner C.

    2012-01-01

    In vivo effects of GABAB receptor-positive modulators suggest them to have therapeutic potential to treat central nervous system disorders such as anxiety and drug abuse. Although these effects are thought to be mediated by positive modulation of GABAB receptors, such modulation has been examined primarily in vitro. This study further examined the in vivo properties of the GABAB receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-t...

  9. Preparation of (+)- and (-)- β-phenyl- and β-(4-chlorophenyl)-γ- butyro lactones: Key intermediates in the synthesis of β-phenyl-Gaba and baclofene

    Energy Technology Data Exchange (ETDEWEB)

    Gomez G, J.; Melendez R, M.; Suarez C, O. R.; Castelan D, L. E.; Fragoso V, M. J.; Lopez V, E.; Sanchez Z, M., E-mail: melendez@uaeh.edu.mx [Universidad Autonoma del Estado de Hidalgo, Area Academica de Quimica, Carretera Pachuca-Tulancingo Km. 4.5, Mineral de la Reforma 42184, Hidalgo (Mexico)

    2014-07-01

    the preparation of β-phenyl- and β-(4-chlorophenyl)-γ-butyro lactones (±)-4 and their resolution to the corresponding (+)-(S)-3, (-)-(R)-3 and (+)-(S)-4, (-)-(R)-4 through formation, flash column chromatography separation and subsequent hydrolysis of dia stereoisomeric 4-hydroxybutyramide s (2'R,3S)-5, (2'R,3R)-5, (2'R,3S)-6 and (2'R,3R)-6 is described. The absolute configuration assignment of enantiopure 3 and 4 was supported by X-ray crystallographic structures of (2'R,3R)-5, (2'R,3S)-6 and (2'R,3R)-6. (Author)

  10. Effect of Baclofen on Spasticity in Spinal Cord Injury: 136 Cases Report%Baclofen治疗脊髓损伤后痉挛的疗效观察

    Institute of Scientific and Technical Information of China (English)

    刘根林; 李建军; 周红俊; 郑樱; 郝春霞; 汪家琮

    2008-01-01

    目的 观察脊髓损伤性痉挛患者口服Baclofen的解痉效果.方法 136例患者连续服药2个月.采用改良Ashworth评分进行评定.结果 改良Ashworth评分降低超过1级的131例(96.3%).结论 该药对不同年龄、性别、损伤部位、损伤程度和损伤时间的患者均有明显的解痉效果,长期服药对肝肾功能无影响.

  11. 过量巴氯芬导致的酷似脑死亡的昏迷%Coma mimicking brain death following baclofen overdose

    Institute of Scientific and Technical Information of China (English)

    李志军; 张苏明

    2001-01-01

    巴氯芬中毒可能是引起脑干功能失调,产生酷似脑死亡的深昏迷的一种原因.这种情况是一种临床诊断,有时血清浓度测不到而且结果也可能产生误导.影像结果往往正常.脑电图显示一种发放抑制模式.目前尚没有特效的治疗方法.然而,正如在我们病例中显示的,即使是很严重的病例,如果能尽早识别并给予恰当的支持治疗,预后较好.

  12. Conformational distribution of baclofen analogues by 1H and 13C NMR analysis and ab initio HF MO STO-3G or STO-3G* calculations

    Science.gov (United States)

    Vaccher, Claude; Berthelot, Pascal; Debaert, Michel; Vermeersch, Gaston; Guyon, René; Pirard, Bernard; Vercauteren, Daniel P.; Dory, Magdalena; Evrard, Guy; Durant, François

    1993-12-01

    The conformations of 3-(substituted furan-2-yl) and 3-(substituted thien-2-yl)-γ-aminobutyric acid 1-9 in solution (D 2O) are estimated from high-resolution (300 MHz) 1H NMR coupling data. Conformations and populations of conformers are calculated by means of a modified Karplus-like relationship for the vicinal coupling constants. The results are compared with X-ray crystallographic investigations (torsion angles) and ab initio HF MO ST-3G or STO-3G* calculations. 1H NMR spectral analysis shows how 1-9 in solution retain the preferred g- conformation around the C3C4 bond, as found in the solid state, while a partial rotation is set up around the C2C3 bond: the conformations about C2C3 are all highly populated in solution. The 13C spin-lattice relaxation times are also discussed.

  13. Birth Defects: Cerebral Palsy

    Science.gov (United States)

    ... to help relax muscle spasms, including: Diazepam (Valium®), baclofen (Lioresal®), dantrolene (Dantrium®) and tizanidine (Zanaflex®). Your child takes these by mouth. Baclofen, a medicine that your child gets through a ...

  14. Neurodegeneration with Brain Iron Accumulation

    Science.gov (United States)

    ... of dystonia and spasticity, including oral medications, intrathecal baclofen pump (in which a small pump is implanted ... of dystonia and spasticity, including oral medications, intrathecal baclofen pump (in which a small pump is implanted ...

  15. Hypertonia

    Science.gov (United States)

    ... Full Definition Treatment Muscle relaxing drugs such as baclofen, diazepam, and dantrolene may be prescribed to reduce ... these drugs can be taken by mouth, but baclofen may also be injected directly into the cerebrospinal ...

  16. Machado-Joseph Disease

    Science.gov (United States)

    ... many years. Treatment with antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can also ... many years. Treatment with antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can also ...

  17. GABA-B receptor activation and conflict behavior

    Energy Technology Data Exchange (ETDEWEB)

    Ketelaars, C.E.J.; Bollen, E.L.; Rigter, H.; Bruinvels, J.

    1988-01-01

    Baclofen and oxazepam enhance extinction of conflict behavior in the Geller-Seifter test while baclofen and diazepam release punished behavior in Vogel's conflict test. In order to investigate the possibility that the effect of the selective GABA-B receptor agonist baclofen is mediated indirectly via the GABA-A/benzodiazepine receptor complex, the effect of pretreatment of rats with baclofen on (/sup 3/H)-diazepam binding to washed and unwashed cortical and cerebellar membranes of rats has been studied. Baclofen pretreatment increase Bmax in washed cerebellar membranes when bicuculline was present in the incubation mixture. No effect was seen in cortical membranes. The present results render it unlikely that the effect of baclofen on extinction of conflict behavior and punished drinking is mediated via the GABA-A/benzodiazepine receptor complex. 50 references, 1 figure, 4 tables.

  18. PIRACETAM AND ANIRACETAM ANTAGONISM OF CENTRALLY ACTIVE DRUG-INDUCED ANTINOCICEPTION

    OpenAIRE

    1996-01-01

    The effects of the nootropic drugs piracetam and aniracetam on antinociception induced by baclofen, bicuculline, and picrotoxin and on baclofen-induced muscle relaxation were studied in mice. Antinociception was investigated using both the hot plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Both behaviour inhibition and muscle relaxation were observed by using the rota-rod test. Piracetam (30 mg/kg, IP) and aniracetam (10 mg/kg, PO) reduced baclofen, bicuculline...

  19. Electroacupuncture Enached Analgesic Effects of Muscimol and Baclofen Microinjected in Hippocampus%电针加强海马微量注射蝇蕈碱与氯苯氨丁酸的镇痛作用

    Institute of Scientific and Technical Information of China (English)

    胡宗礼; 黄晓萍

    2001-01-01

    目的 观察电针对大鼠海马微量注射GABA受体激动剂蝇蕈碱(Mus)和氯苯氨丁酸(Bac)镇痛作用的影响。方法 实验分生理盐水对照组、药物组和电针+药物组,在2分钟内将1μl Mus或Bac(1×10-3mol.L-1)注射入海马,取双侧足三里进行电针,用甩尾法测定大鼠的痛阈。结果 从给药后5min至60min,Mus或Bac均能明显提高大鼠的痛阈(P<0.01),20min时作用最显著,痛阈分别提高0.386±0.062mA和0.549±0.116mA。电针能加强Mus和Bac的镇痛作用(P<0.05或P<0.01),痛阈最大提高值分别为0.603±0.117mA和0.704±0.099mA。结论 海马微量注射Mus或Bac能产生镇痛作用,并且电针能加强其镇痛作用。

  20. HPLC手性流动相添加剂法拆分巴氯芬对映体%Chiral separation of baclofen enantiomers by HPLC withchiral mobile phase additives

    Institute of Scientific and Technical Information of China (English)

    卢建国; 王立艳; 苏立强

    2011-01-01

    建立了以羧甲基-β-环糊精为手性流动相添加剂,在反相液谱条件下拆分巴氯芬对映体的方法.研究了手性添加剂的种类及浓度、流动相组成、pH值及流速等因素对拆分的影响.流动相为甲醇、乙腈、水,体积比为90∶5∶5,其中含2.00g/L CM-β-CD,pH值5.95,流速0.60mL/min,检测波长231 nm,分离度为1.31.该方法简便、快速、相对偏差小.

  1. A preliminary study on Baclofen in treatment of spastic cerebral palsy%巴氯芬治疗痉挛型小儿脑性瘫痪的初步探讨

    Institute of Scientific and Technical Information of China (English)

    李林; 林萍; 姜志梅

    2000-01-01

    目的探讨巴氯芬治疗痉挛型小儿脑性瘫痪的效果.方法对确诊的50例患儿按年龄给药,剂量为每日40~75 mg,逐渐增量,10~15 d为1疗程,分级标准采用改良的Ashuorth评分法.结果显效3例,有效12例,好转20例,总有效为35例,总有效率70%.并且1~3岁与4~6岁两年龄组间存在显著性差异(P<0.001).结论巴氯芬是目前降低痉挛型脑瘫患儿肌张力最有效的方法之一,且年龄越小,效果越好,同时应严密观察其副作用.

  2. 液相色谱串联质谱法测定猪肉和猪尿中巴氯芬%Determination of Baclofen in Pork and Swine Urine by Liquid Chromatograpy Tandem Mass Spectrometry

    Institute of Scientific and Technical Information of China (English)

    许秀琴; 吴银良; 杨挺; 朱勇; 赵健; 叶宇飞

    2013-01-01

    样品中的巴氯芬用0.01 mol/L HCl溶液提取,提取液经WCX柱净化、富集后,进行液相色谱串联质谱(LC/MS-MS)分析.分析时采用BEH C18色谱柱(100mm×2.1mm,1.7μm),以0.10%甲酸水/甲醇作为流动相进行梯度洗脱,电喷雾正电子(ESI+)模式电离,多反应监测(MRM)模式检测,内标法进行定量.结果表明:巴氯芬标准溶液在1.0~100.0μg/L范围内,峰面积与含量呈线性相关.猪肉和猪尿中巴氯芬检出限分别为0.30μg/kg和0.10μg/L,两种样品中添加回收率在85%~110%之间,相对标准偏差(RSD)小于10%.

  3. GABAB受体激动剂巴氯酚重复注射对大鼠血压的影响%Effects of repeated injection of GABAB receptor agonist baclofen on mean blood pressure in rats

    Institute of Scientific and Technical Information of China (English)

    刘翠清; 林国华

    2006-01-01

    目的 观察GABAB受体激动剂-巴氯酚二次重复注射对大鼠血压的影响.方法 对氨基甲酸乙酯麻醉的大鼠行巴氯酚二次重复腹腔注射,通过股动脉插管记录血压,比较两次注射后血压的变化.结果 首次注入后血压由(113.2±8.3)mmHg显著升至(139.2±11.2)mmHg(P<0.05)并维持;60min后行第二次巴氯酚注射,血压却显著降至(120.3±20.4)mmHg,与首次注射前血压无显著性差异(P>0.05).结论 巴氯酚重复注射翻转了首次注射的升压效应,原因可能与受体内化有关.

  4. Effect of Herbal Fumigation with Baclofen on Spasm Hemiplegia after Stroke%中药熏蒸结合巴氯芬治疗脑卒中偏瘫痉挛临床观察

    Institute of Scientific and Technical Information of China (English)

    陈佳; 张国庆; 周湘明; 杨春桥

    2010-01-01

    目的 观察中药熏蒸结合巴氯芬治疗脑卒中偏瘫痉挛的临床疗效.方法 50例患者随机分为观察组(巴氯芬)和治疗组(中药熏蒸结合巴氯芬),每组各25例,并给予相应治疗,疗程30 d.观察痉挛临床疗效、经修改的Ashworth量表痉挛程度评定变化.结果 治疗组患肢肌张力改善总有效率高于对照组(P<0.05).结论 中药熏蒸结合巴氯芬治疗法能有效减轻脑卒中偏瘫肢体痉挛.

  5. Baclofen与异搏停治疗脊髓损伤后痉挛性膀胱的对比研究%Comparative study on Baclofen and Verapamil in the treatment of spastic bladder after spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    刘明轩; 侯春林; 邱实

    2000-01-01

    目的:观察Baclofen与异搏停治疗脊髓完全性损伤后痉挛性膀胱的疗效并进行比较分析.方法:将32例脊髓损伤后痉挛性膀胱患者按随机抽样法分为Baclofen组和异搏停组,分别于用药后2、4、8周观察膀胱功能变化,并进行尿流动力学检测.结果:两组患者用药后排尿间隔延长、排尿量增加、尿道压力降低,膀胱贮尿及排尿功能均较用药前明显提高,Baclofen组优于异搏停组.结论:Baclofen与异搏停治疗脊髓损伤后痉挛性膀胱疗效显著,Baclofen可做为首选用药.

  6. Clinical observation of baclofen for treatment of postherpetic neuralgia%巴氯芬治疗带状疱疹感染后神经痛的临床观察

    Institute of Scientific and Technical Information of China (English)

    范红杰; 于维东

    2005-01-01

    目的观察巴氯芬治疗带状疱疹感染后神经痛的疗效.方法69例带状疱疹感染后神经痛的患者随机分为治疗组(37例)、对照纽(32例).治疗组服用巴氯芬,对照组服用卡马西平,其他治疗两组相同,治疗1个月后疗效评价.结果治疗前两组患者年龄、性别、病程、神经痛分布区域无显著性差异,具有可比性.治疗后治疗组总有效率86.49%,明显高于对照组65.63%,且副作用少.结论巴氯芬可作为治疗带状疱疹感染后神经痛的首选药物.

  7. 鞘内注射巴氯酚在治疗脑性瘫痪儿童痉挛中的应用%Application of intrathecal baclofen in the treatment of spasticity in children with cerebral palsy

    Institute of Scientific and Technical Information of China (English)

    蔡斌; 陈博昌

    2004-01-01

    鞘内注射巴氯酚由于作用持久,全身副作用轻等优点被应用于治疗脑瘫儿童痉挛.介绍了鞘内注射巴氯酚的原理及其实施方法.综述了鞘内注射巴氯酚治疗脑瘫儿童上肢或下肢痉挛的有效性和安全性的文献(含非对照性研究和对照性研究) , 鞘内注射巴氯酚是一种有效的缓解脑瘫痉挛的疗法.

  8. Badofen对大鼠脊髓薄片胶状质神经元的抑制作用%Inhibitory effects of baclofen upon substantia gelatinosa neurons in rat spinal cord slice

    Institute of Scientific and Technical Information of China (English)

    闫励; 杨鲲; 冯宇鹏; 赵华; 李云庆

    2001-01-01

    用脊髓薄片全细胞电压钳法观察激活γ-氨基丁酸B亚型受体(GABABR)对大鼠脊髓背角胶状质(SG)神经元活动的影响.选择性GABABR激动剂baclofen减少所有被记录SG神经元(n=15)的微小兴奋性突触后电流(mEPSCs)的发放频率,同时引起一缓慢的抑制性(外向)膜电流并伴有膜电导增加.细胞内电泳G蛋白偶联受体抑制剂(GDP-β-S)抑制被钳制神经元的G蛋白偶联受体后,baclofen引起的缓慢外向电流被抑制,但对mEPSC频率的减低作用依然存在.结果提示脊髓内baclofen敏感的GABAB受体被激活后直接引起SG神经元超极化并能减少突触前递质的释放.

  9. 影响巴氯芬缓解脑源性肌痉挛效果的原因分析%Cause analysis of weakening Baclofen effect in treating brain-derived muscular spasm

    Institute of Scientific and Technical Information of China (English)

    杨远滨; 李广庆; 屈亚平; 王茂斌

    2004-01-01

    目的:分析影响巴氯芬缓解脑源性肌痉挛效果的原因,探讨巴氯芬应用中的注意事项.方法:选择2003-01/2004-07首都医科大学宣武医院收治的30例服用巴氯芬缓解脑源性肌痉挛效果不佳的病例进行分析,服药前后以改良Asworth评分测定肌张力,运用SPSS11.1统计软件进行处理,同时分析其可能原因.结果:治疗前评分(4.33±0.66)分,治疗后评分(4.23±0.77)分,差异无显著性意义,表明服药前后痉挛缓解不明显.分析其原因为:①重度中枢神经系统损伤.②挛缩.③骨折.④脑积水.⑤副反应过强.⑥异位骨化.⑦癫痫.⑧深静脉血栓.结论:巴氯芬对较重的痉挛效果不理想,而轻、中度痉挛效果较好,故痉挛治疗应综合进行,早期合理体位摆放,减少痉挛出现,预防挛缩,防止异位骨化,早筛查发现骨折,尤其对脑损伤患者应及时监测脑室压力变化.另外不要忘记治疗原发病,改善脑功能状态.

  10. Pharmacology of the GABAB receptor in amphibian retina.

    Science.gov (United States)

    Tian, N; Slaughter, M M

    1994-10-17

    Amacrine and ganglion cells in the amphibian retina contain GABAB, as well as GABAA, receptors. Baclofen, a GABAB agonist, hyperpolarizes the dark membrane potential of these third order neurons and makes their light responses more transient. GABAB receptors in the retina have a similar agonist profile to GABAB receptors described at other sites in the brain. Namely, preferential activation by the R-enantiomer of baclofen, and agonist sensitivity in the order 3-aminopropylphosphinic acid > baclofen > 3-aminopropylphosphonic acid. The GABAB receptor was not activated by 4-aminobutylphosphonic acid. Several antagonists, such as phaclofen, saclofen, and 2-hydroxysaclofen, were ineffective in the amphibian retina. However, CGP35348 blocked the action of applied baclofen and produced effects on the light response that were opposite to those of baclofen. Applied agonists and antagonists support the hypothesis that GABAB receptors serve to regulate the balance of sustained and transient signals to the inner retina.

  11. Activation of GABA B receptors in the anterior pituitary inhibits prolactin and luteinizing hormone secretion.

    Science.gov (United States)

    Lux-Lantos, V; Rey, E; Libertun, C

    1992-11-01

    Previous work from our laboratory showed that baclofen could lower serum prolactin (PRL) levels acting at the central nervous system. The present experiments were designed to evaluate whether the gamma-aminobutyric acid B agonist was also effective in inhibiting hormone release at the pituitary level. In monolayer cultures of adenohypophyseal dispersed cells, baclofen inhibited basal PRL secretion after 1 or 2 h of incubation. This inhibition was significantly abolished by three antagonists: phaclofen, 3-aminopropyl-phosphonic acid and 4-aminobutylphosphonic acid. Furthermore, baclofen inhibited the thyrotropin-releasing hormone-induced PRL release in a concentration-dependent manner. With regard to gonadotropin secretion, baclofen was unable to modify basal luteinizing hormone (LH) secretion, but significantly inhibited the LH-releasing hormone-induced LH release. These results show that baclofen, in addition to its central neuroendocrine effects, inhibits pituitary hormone secretion, under basal and/or stimulated conditions, by direct action at the pituitary level.

  12. Intratekal baclofenbehandling ved svaer spastisk tetraplegi og dystoni hos børn og unge

    DEFF Research Database (Denmark)

    Illum, Niels Ove; Hansen, Flemming Juul; Fischer, Claudia;

    2003-01-01

    with baclofen, tizanidine, dantrolene and/or diazepam. Intrathecal baclofen has therefore been applied in a group of young patients. MATERIAL AND METHODS: Eight children and young adults from East Denmark with spasticity and 12 with dystonia aged 3-18 years (median 10.9 years) were tested, operated and treated......INTRODUCTION: Continuous intrathecal baclofen has been used over the past years especially in adult patients with spasticity of spinal origin. Children and young adults with severe spasticity and dystonia of cerebral origin are difficult to treat in spite of optimal systemic antispasmotic therapy...... out of 19 patients, and less pain in 13 out of 19 patients. CONCLUSION: Continuous intrathecal baclofen was effective in treating severe spasticity and dystonia of cerebral origin with major effect on muscles of the lower extremities, pelvis, and back and in particular opisthotonus was relieved...

  13. Chronic Idiopathic Cough and Chronic Cough in Idiopathic Pulmonary Fibrosis | EU Clinical Trials Register [EU Clinical Trials Register

    Lifescience Database Archive (English)

    Full Text Available nhaled corticosteroids, benzonatate, dextromethorphan, carbetapentane, H1 antihistamines, leukotriene modifi...eeks of the Screening Visit: Prednisone, narcotic antitussives, baclofen, gabapentin, inhaled corticosteroids, benzonatate, dextromet...horphan, carbetapentane, H1 antihistamines, leukotriene

  14. Editorial

    Directory of Open Access Journals (Sweden)

    Dominika Dudek

    2015-04-01

    methods which help to reduce the degree of alcohol abuse and the resulting damage. These include: acamprosate, drugs which are opioid receptor antagonists [2], and in the current issue the authors from the University of Cagliari focused on baclofen. (...

  15. The clinical observation of "baclofen" on the anti-spastic effect of acute paroxysm of lumbar intervertebral disc herniation%巴氯芬对腰椎间盘突出症急性发作期抗痉挛作用的临床观察

    Institute of Scientific and Technical Information of China (English)

    施问民

    2005-01-01

    目的探讨巴氯芬对改善腰突症急性发作期的肌痉挛症状的效果.方法观察组采用理疗加药物:(1)理疗:腰椎牵引+电脑中频,每天一次,每次各20min.(2)药物:选用国产巴氯芬(枢芬),起始剂量每次5mg,每天三次,酌情每三天增加5mg/d,可加至30mg/d.对照组为腰椎牵引加电脑中频.以上二组均10d为一疗程,共观察二个疗程.结果经过二个疗程的治疗后,二组患者整体水平均有提高,但观察组各项指标均优于对照组.结论在腰突症急性期有肌痉挛症状者,不失时机地介入巴氯芬治疗,对缓解肌痉挛,提高康复疗效是有价值的.

  16. Severe Seizures During Propofol Induction in a Patient with Syringomyelia Receiving Baclofen%服用巴氯芬的脊髓空洞症患者丙泊酚诱导时癫痫大发作一例报道

    Institute of Scientific and Technical Information of China (English)

    Sethuraman Manikandan; Prabhat K.Sinha; Praveen K.Neema; Ramesh C.Rathod; 任飞

    2006-01-01

    我们报道一例服用巴氯芬治疗曲肌痉挛的脊髓空洞症患者在神经外科手术前使用丙泊酚麻醉诱导时反复出现癫痫全身性大发作,并对丙泊酚和巴氯芬在该病例癫痫发作中可能的相互作用进行了讨论.

  17. GABA B receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneurons.

    Science.gov (United States)

    Lei, Saobo; McBain, Chris J

    2003-01-15

    Hippocampal stratum radiatum inhibitory interneurons receive glutamatergic excitatory innervation via the recurrent collateral fibers of CA3 pyramidal neurons and GABAergic inhibition from other interneurons. We examined both presynaptic- and postsynaptic-GABA(B) receptor-mediated responses at both synapse types. Postsynaptic GABA(B) receptor-mediated responses were absent in recordings from young (P16-18) but present in recordings from older animals (> or =P30) suggesting developmental regulation. In young animals, the GABA(B) receptor agonist, baclofen, inhibited the amplitude of evoked EPSCs and IPSCs, an effect blocked by prior application of the selective antagonist CGP55845. Baclofen enhanced the paired-pulse ratio and coefficient of variation of evoked EPSCs and IPSCs, consistent with a presynaptic mechanism of regulation. In addition, baclofen reduced the frequency of miniature IPSCs but not mEPSCs. However, baclofen reduced the frequency of KCl-induced mEPSCs; an effect blocked by Cd(2+), implicating presynaptic voltage-gated Ca(2+) channels as a target for baclofen modulation. In contrast, although Cd(2+) prevented the KCl-induced increase in mIPSC frequency, it failed to block baclofen's reduction of mIPSC frequency. Whereas N- and P/Q-types of Ca(2+) channels contributed equally to GABA(B) receptor-mediated inhibition of EPSCs, more P/Q-type Ca(2+) channels were involved in GABA(B) receptor-mediated inhibition of IPSCs. Finally, baclofen blocked the frequency-dependent depression of EPSCs and IPSCs, but was less effective at blocking frequency-dependent facilitation of EPSCs. Our results demonstrate that presynaptic GABA(B) receptors are expressed on the terminals of both excitatory and inhibitory synapses onto CA3 interneurons and that their activation modulates essential components of the release process underlying transmission at these two synapse types.

  18. Dual effect of GABA on descending monosynaptic excitatory postsynaptic potential in frog lumbar motoneurons.

    Science.gov (United States)

    Ovsepian, S V; Vesselkin, N P

    2004-01-01

    Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked by stimulating ipsilateral ventrolateral column (VLC) in the thoracic section were recorded in lumbar motoneurons within the isolated spinal cord of the frog Rana ridibunda. Bath application of the selective GABAB receptor agonist (-)-baclofen (0.05 mM) caused a reduction in the peak amplitude of VLC EPSP. Baclofen did not cause any consistent change in the membrane potential or in the EPSP waveform within frog motoneurones. The selective GABA(B) receptor antagonist saclofen (0.1 mM) completely blocked the effect of (-)-baclofen on VLC EPSP. A decrease in VLC EPSP peak amplitude was also observed during GABA (0.5 mM) application. Unlike (-)-baclofen, inhibition of VLC EPSP induced by GABA was accompanied by a shortening of the EPSP time course and a reduction in membrane input resistance within lumbar motoneurons. The decrease in VLC EPSP peak amplitude induced by (-)-baclofen and GABA was accompanied by an increase in the paired-pulse facilitation. These data provide evidence for a dual pre- and postsynaptic GABAergic inhibition of the VLC monosynaptic EPSP in lumbar motoneurons within the frog spinal cord.

  19. The role of GABAB receptors in human reinforcement learning.

    Science.gov (United States)

    Ort, Andres; Kometer, Michael; Rohde, Judith; Seifritz, Erich; Vollenweider, Franz X

    2014-10-01

    Behavioral evidence from human studies suggests that the γ-aminobutyric acid type B receptor (GABAB receptor) agonist baclofen modulates reinforcement learning and reduces craving in patients with addiction spectrum disorders. However, in contrast to the well established role of dopamine in reinforcement learning, the mechanisms by which the GABAB receptor influences reinforcement learning in humans remain completely unknown. To further elucidate this issue, a cross-over, double-blind, placebo-controlled study was performed in healthy human subjects (N=15) to test the effects of baclofen (20 and 50mg p.o.) on probabilistic reinforcement learning. Outcomes were the feedback-induced P2 component of the event-related potential, the feedback-related negativity, and the P300 component of the event-related potential. Baclofen produced a reduction of P2 amplitude over the course of the experiment, but did not modulate the feedback-related negativity. Furthermore, there was a trend towards increased learning after baclofen administration relative to placebo over the course of the experiment. The present results extend previous theories of reinforcement learning, which focus on the importance of mesolimbic dopamine signaling, and indicate that stimulation of cortical GABAB receptors in a fronto-parietal network leads to better attentional allocation in reinforcement learning. This observation is a first step in our understanding of how baclofen may improve reinforcement learning in healthy subjects. Further studies with bigger sample sizes are needed to corroborate this conclusion and furthermore, test this effect in patients with addiction spectrum disorder.

  20. GABA/sub B/ receptor activation inhibits Ca/sup 2 +/-activated potassium channels in synaptosomes: involvement of G-proteins

    Energy Technology Data Exchange (ETDEWEB)

    Ticku, M.K.; Delgado, A.

    1989-01-01

    /sup 86/Rb-efflux assay from preloaded synaptosomes of rat cerebral cortex was developed to study the effect of GABA/sub B/ receptor agonist baclofen on Ca/sup 2 +/-activated K/sup +/-channels. Depolarization of /sup 86/Rb-loaded synaptosomes in physiological buffer increased Ca/sup 2 +/-activated /sup 86/Rb-efflux by 400%. The /sup 86/Rb-efflux was blocked by quinine sulfate, tetraethylammonium, and La/sup 3 +/ indicating the involvement of Ca/sup 2 +/-activated K/sup +/-channels. (-)Baclofen inhibited Ca/sup 2 +/-activated /sup 86/Rb-efflux in a stereospecific manner. The inhibitory effect of (-)baclofen was mediated by GABA/sub B/ receptor activation, since it was blocked by GABA/sub B/ antagonist phaclofen, but not by bicuculline. Further, pertussis toxin also blocked the ability of baclofen or depolarizing action to affect Ca/sup 2 +/-activated K/sup +/-channels. These results suggest that baclofen inhibits Ca/sup 2 +/-activated K/sup +/-channels in synaptosomes and these channels are regulated by G-proteins. This assay may provide an ideal in vitro model to study GABA/sub B/ receptor pharmacology.

  1. Electrical and pharmacological neuromodulation in patient with spinal cord injury pain (La neuromodulazione elettrica e farmacologica nel paziente con dolore post lesione midollare

    Directory of Open Access Journals (Sweden)

    Carmelo Costa

    2014-10-01

    Full Text Available The authors present the different kinds of pain following the spinal cord lesions (neuropathic, nociceptive, somatic, visceral; they describe the alterations that occur on spinal cord, brain and periphery; the methods to define the kinds of pain and to evaluate the pain intensity; the strumental and pharmacological treatments for pain relief. In detail data on the efficacy of spinal neurostimulation are compared with data on the efficacy of baclofen intrathecally administered. Based on results of his studies and on international literature data, the authors conclude that efficacy of treatment with baclofen intratecally administered with a programmable pump is higher than spinal neurostimulation treatment.

  2. GABAB antagonists

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Hansen, J J; Krogsgaard-Larsen, P

    1994-01-01

    Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chroma...

  3. Spasticity : Revisiting the role and the individual value of several pharmacological treatments

    NARCIS (Netherlands)

    Lapeyre, Eric; Kuks, Jan B. M.; Meijler, Andwillem J.

    2010-01-01

    Though in the last few decades only a few new drugs have come available for the treatment of spasticity, new insights may revise the role and individual value of several pharmacological treatments. Diazepam, baclofen and tizanidine are the most prescribed drugs for the treatment of spasticity. Intra

  4. Drug: D09791 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available fragile X syndrome and autism prodrug, active substance: Baclofen [DR:D00241] GABA-B receptor agonist [HSA:...D09791 Drug Arbaclofen (USAN) C10H12ClNO2 213.0557 213.6608 D09791.gif Treatment of

  5. The effects of centrally acting muscle relaxants on the intrathecal noradrenaline-induced facilitation of the flexor reflex mediated by group II afferent fibers in rats.

    Science.gov (United States)

    Sakitama, K

    1993-11-01

    The effects of centrally acting muscle relaxants on the flexor reflex mediated by group II afferent fibers (group II flexor reflex) in anesthetized intact rats and on the intrathecal noradrenaline-HCl-induced facilitation of the group II flexor reflex in anesthetized spinal rats were investigated. In anesthetized intact rats, mephenesin, tolperisone-HCl, chlorpromazine-HCl and baclofen inhibited the group II flexor reflex dose-dependently, whereas the inhibitory effect of tizanidine-HCl was bell-shaped. The effect of diazepam tended to be saturated. In anesthetized spinal rats, mephenesin, tolperisone-HCl, chlorpromazine-HCl, diazepam and baclofen also depressed the group II flexor reflex, but tizanidine-HCl slightly increased it. The intrathecal noradrenaline-HCl-induced facilitation of the group II flexor reflex was not affected by mephenesin or diazepam, but was inhibited by tizanidine-HCl, tolperisone-HCl, chlorpromazine-HCl and baclofen. These results suggest that compounds with centrally acting muscle relaxant activity depress the group II flexor reflex in different manners, and the inhibition of descending noradrenergic tonic facilitation within the spinal cord participates in the depressant action of the group II flexor reflex produced by tolperisone-HCl, tizanidine-HCl, chlorpromazine-HCl and baclofen.

  6. Activation of the GABAB receptor prevents nicotine-induced locomotor stimulation in mice

    Directory of Open Access Journals (Sweden)

    Carla eLobina

    2011-12-01

    Full Text Available Recent studies demonstrated that activation of the GABAB receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs, inhibited different nicotine-related behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABAB receptor agonist, baclofen, and GABAB PAMs, CGP7930 and GS39783, extend to nicotine stimulant effects. To this end, CD1 mice were initially treated with baclofen (0, 1.25, and 2.5 mg/kg, i.p., CGP7930 (0, 25, and 50 mg/kg, i.g., or GS39783 (0, 25, and 50 mg/kg, i.g., then treated with nicotine (0 and 0.05 mg/kg, s.c., and finally exposed to an automated apparatus for recording of locomotor activity. Pretreatment with doses of baclofen, CGP7930, or GS39783 that did not alter locomotor activity when given with nicotine vehicle fully prevented hyperlocomotion induced by 0.05 mg/kg nicotine. These data extend to nicotine stimulant effects the capacity of baclofen and GABAB PAMs to block the reinforcing, motivational, and rewarding properties of nicotine. These data strengthen the hypothesis that activation of the GABAB receptor may represent a potentially useful, anti-smoking therapeutic strategy.

  7. Treatment of acquired periodic alternating nystagmus with memantine: a case report.

    Science.gov (United States)

    Kumar, Anil; Thomas, Shery; McLean, Rebecca; Proudlock, Frank A; Roberts, Eryl; Boggild, Mike; Gottlob, Irene

    2009-01-01

    We report a case of acquired periodic alternating nystagmus associated with common variable immunodeficiency and cutaneous sarcoid. The patient was initially treated with baclofen with minimal subjective improvement. We found a significant improvement in the patient's symptoms and nystagmus intensity after treatment with memantine.

  8. Pharmacological characterization of homobaclofen on wild type and mutant GABA(B)1b receptors coexpressed with the GABA(B)2 receptor

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Madsen, Bo E.; Krogsgaard-Larsen, P;

    2001-01-01

    Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) receptor agonist baclofen. In a recent study, the two enantiomers of this compound were tested in a GABA(B) receptor selective [3H]gamma-aminobutyric acid ([3H]GABA) binding assay using rat brain homo...

  9. Evaluation of the Effects of Sativex (THC BDS: CBD BDS) on Inhibition of Spasticity in a Chronic Relapsing Experimental Allergic Autoimmune Encephalomyelitis: A Model of Multiple Sclerosis.

    Science.gov (United States)

    Hilliard, A; Stott, C; Wright, S; Guy, G; Pryce, G; Al-Izki, S; Bolton, C; Giovannoni, G

    2012-01-01

    This study investigated the antispasticity potential of Sativex in mice. Chronic relapsing experimental allergic encephalomyelitis was induced in adult ABH mice resulting in hind limb spasticity development. Vehicle, Sativex, and baclofen (as a positive control) were injected intravenously and the "stiffness" of limbs assessed by the resistance force against hind limb flexion. Vehicle alone caused no significant change in spasticity. Baclofen (5 mg/kg) induced approximately a 40% peak reduction in spasticity. Sativex dose dependently reduced spasticity; 5 mg/kg THC + 5 mg/kg CBD induced approximately a 20% peak reduction; 10 mg/kg THC + 10 mg/kg CBD produced approximately a 40% peak reduction in spasticity. Sativex has the potential to reduce spasticity in an experimental mouse model of multiple sclerosis (MS). Baclofen reduced spasticity and served as a positive control. Sativex (10 mg/kg) was just as effective as baclofen, providing supportive evidence for Sativex use in the treatment of spasticity in MS.

  10. Regulation of /sup 3/H-dopamine release by presynaptic GABA and glutamate heteroreceptors in rat brain nucleus accumbens synaptosomes

    Energy Technology Data Exchange (ETDEWEB)

    Kovalev, G.I.; Hetey, L.

    1987-06-01

    The aim of this investigation was a neurochemical study of the effect of agonists of different types of GABA receptors - muscimol (type A receptor), baclofen (type B receptor), delta-aminolevulinic acid (DALA; GABA autoreceptor), and also of GABA itself - on tritium-labelled dopamine release, stimulated by potassium cations, from synaptosomes of the nuclei accumbenes of the rat brain.

  11. Complex regional pain syndrome related dystonia : exploratory metabolomics and therapeutic studies

    NARCIS (Netherlands)

    Plas, Anton Adriaan van der

    2013-01-01

    Dit proefschrift beschrijft de resultaten van aan aantal studies naar bewegingsstoornissen en pijn bij patiënten met complex regionaal pijnsyndroom (CRPS). Ten eerste werd het effect onderzocht van intrathecaal baclofen op verschillende pijnkwaliteiten bij CRPS-patiënten, de invloed bestudeerd van v

  12. GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence

    Directory of Open Access Journals (Sweden)

    Roberta eAgabio

    2014-06-01

    Full Text Available The present paper summarizes the preclinical and clinical studies conducted to define the anti-alcohol pharmacological profile of the prototypic GABAB receptor agonist, baclofen, and its therapeutic potential for treatment of alcohol use disorder (AUD. Numerous studies have reported baclofen-induced suppression of alcohol drinking (including relapse- and binge-like drinking and alcohol reinforcing, motivational, stimulating, and rewarding properties in rodents and monkeys. The majority of clinical surveys conducted to date – including case reports, retrospective chart reviews, and randomized placebo-controlled studies – suggest the ability of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. The recent identification of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, represents a novel, and likely more favorable, option for pharmacological manipulations of the GABAB receptor. Accordingly, data collected to date suggest that positive allosteric modulators of the GABAB receptor reproduce several anti-alcohol effects of baclofen and display a higher therapeutic index (with larger separation – in terms of doses – between anti-alcohol effects and sedation.

  13. Venovenøs hæmodiafiltrering til baclofenforgiftet patient

    DEFF Research Database (Denmark)

    Nielsen, Simon Uhl; Jansen, Tejs; Johansen, Sys Stybe;

    2011-01-01

    Twice a young man was admitted to hospital upon having taken baclofen overdoses by intention. The ingested dose was 1,850 mg at the first episode and up to 2,500 mg at the second. In both cases the patient had severe overdose symptoms and scored 4-5 on the Glascow Coma Scale and was admitted to i...

  14. Patterns of connectivity of spinal interneurons with single muscle afferents.

    Science.gov (United States)

    Quevedo, J; Eguibar, J R; Lomeli, J; Rudomin, P

    1997-07-01

    A technique was developed to measure, in the anesthetized and paralyzed cat under artificial ventilation, changes of excitability to intraspinal stimulation simultaneously in two different afferent fibers or in two collaterals of the same afferent fiber. Intraspinal stimulation reduced the threshold of single muscle afferent fibers ending in the intermediate nucleus. This effect was seen with strengths below those required to activate the afferent fiber tested (1.5-12 microA), occurred at a short latency (1.5-2.0 ms), reached a maximum between 15 and 30 ms, and lasted up to 100 ms. The effects produced by graded stimulation applied at the shortest conditioning-testing stimulus time intervals increased by fixed steps, suggesting recruitment of discrete elements, most likely of last-order interneurons mediating primary afferent depolarization (PAD). The short-latency increases in excitability produced by the weakest effective intraspinal stimuli were usually detected only in the collateral closest to the stimulating micropipette, indicating that the stimulated interneurons mediating PAD have spatially restricted actions. The short-latency PAD produced by intraspinal stimuli, as well as the PAD produced by stimulation of the posterior biceps and semitendinosus (PBSt) nerve or by stimulation of the bulbar reticular formation (RF), was depressed 19-30 min after the i.v. injection of 0.5 mg/kg of picrotoxin, suggesting that all these effects were mediated by GABAergic mechanisms. The PAD elicited by stimulation of muscle and/or cutaneous nerves was depressed following the i.v. injection of (-)-baclofen, whereas the PAD elicited in the same collateral by stimulation of the RF was baclofen-resistant. The short-latency PAD produced by intraspinal stimulation was not always depressed by i.v. injections of (-)-baclofen. Baclofen-sensitive and baclofen-resistant monosynaptic PADs could be produced in different collaterals of the same afferent fiber. The results suggest that

  15. Involvement of GABA(B) receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats.

    Science.gov (United States)

    Zarrindast, Mohammad-Reza; Massoudi, Roohollah; Sepehri, Houri; Rezayof, Ameneh

    2006-01-30

    In the present study, effects of intra-hippocampal CA1 (intra-CA1) injections of GABA(B) receptor agonist and antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. Subcutaneous administration of different doses of morphine sulphate (0.5-6 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the GABA(B) receptor agonist, baclofen (0.5-2 microg/rat; intra-CA1), or the GABA(B) receptor antagonist, phaclofen (1-3 microg/rat; intra-CA1), did not produce a significant place preference or place aversion. Intra-CA1 administration of baclofen (1 and 2 microg/rat; intra-CA1) decreased the acquisition of CPP induced by morphine (3 mg/kg; s.c.). On the other hand, intra-CA1 injection of phaclofen (1 and 2 microg/rat; intra-CA1) in combination with a lower dose of morphine (1 mg/kg) elicited a significant CPP. The response of baclofen (2 microg/rat; intra-CA1) was reversed by phaclofen (4 and 6 microg/rat; intra-CA1). Furthermore, intra-CA1 administration of baclofen but not phaclofen before testing significantly decreased the expression of morphine (3 mg/kg; s.c.)-induced place preference. Baclofen or phaclofen injections had no effects on locomotor activity on the testing sessions. It is concluded that the GABA(B) receptors in dorsal hippocampus may play an active role in morphine reward.

  16. GABAB receptor-positive modulators: enhancement of GABAB receptor agonist effects in vivo.

    Science.gov (United States)

    Koek, Wouter; France, Charles P; Cheng, Kejun; Rice, Kenner C

    2010-10-01

    In vivo effects of GABA(B) receptor-positive modulators suggest that they have therapeutic potential for treating central nervous system disorders such as anxiety, depression, and drug abuse. Although these effects generally are thought to be mediated by positive modulation of GABA(B) receptors, such modulation has been examined primarily in vitro. The present study was aimed at further examining the in vivo positive modulatory properties of the GABA(B) receptor-positive modulators, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). Both compounds enhanced loss of righting induced by baclofen in mice. However, CGP7930 was less effective and rac-BHFF was less potent for enhancing loss of righting induced by γ-hydroxybutyrate (GHB), which, like baclofen, has GABA(B) receptor agonist properties. In contrast with baclofen- and GHB-induced loss of righting, the hypothermic effects of baclofen and GHB were not enhanced by rac-BHFF but were enhanced by CGP7930 only at doses that produced hypothermia when given alone. CGP7930-induced hypothermia was not attenuated by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348), at doses that blocked baclofen-induced hypothermia, and was not increased by the nitric-oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester, at doses that increased the hypothermic effects of baclofen and GHB. The results provide evidence that CGP7930 and rac-BHFF act in vivo as positive modulators at GABA(B) receptors mediating loss of righting, but not at GABA(B) receptors mediating hypothermia. Conceivably, CGP7930, but not rac-BHFF, acts as an allosteric agonist at these latter receptors. Taken together, the results provide further evidence of pharmacologically distinct GABA(B) receptor subtypes, possibly allowing for a more selective therapeutic interference with the GABA(B) system.

  17. Rhizotomibehandling af børn med svaer spastisk cerebral parese

    DEFF Research Database (Denmark)

    Illum, Niels Ove; Torp-Pedersen, Lisbeth; Midholm, Steen;

    2006-01-01

    INTRODUCTION: Severe spasticity is a limiting factor for motor development in children with spastic cerebral palsy. Botulinum toxin, intrathecal baclofen and peroral baclofen all reduce spasticity but might also limit improvements in functional development over time. In the selective dorsal...... or posterior rhizotomy (SDR) approach, afferent sensory nerve fibers are cut while efferent motor fibers are preserved. In this way spasticity is reduced and motor functions can improve. SDR is an established treatment method, and the first Danish study is reported. MATERIAL AND METHODS: Twenty Danish children......). At 18 months, scores were non-significant (t test, p > 0.05), but at 60 months they were significant (t children had worse post-operative scores and 12 children had better scores. When comparing age at operation with outcome, we observed a certain degree...

  18. Complex regional pain syndrome with associated chest wall dystonia: a case report

    Directory of Open Access Journals (Sweden)

    Schwartzman Robert J

    2011-09-01

    Full Text Available Abstract Patients with complex regional pain syndrome (CRPS often suffer from an array of associated movement disorders, including dystonia of an affected limb. We present a case of a patient with long standing CRPS after a brachial plexus injury, who after displaying several features of the movement disorder previously, developed painful dystonia of chest wall musculature. Detailed neurologic examination found palpable sustained contractions of the pectoral and intercostal muscles in addition to surface allodynia. Needle electromyography of the intercostal and paraspinal muscles supported the diagnosis of dystonia. In addition, pulmonary function testing showed both restrictive and obstructive features in the absence of a clear cardiopulmonary etiology. Treatment was initiated with intrathecal baclofen and the patient had symptomatic relief and improvement of dystonia. This case illustrates a novel form of the movement disorder associated with CRPS with response to intrathecal baclofen treatment.

  19. Comparison of Nootropic and Neuroprotective Features of Aryl-Substituted Analogs of Gamma-Aminobutyric Acid.

    Science.gov (United States)

    Tyurenkov, I N; Borodkina, L E; Bagmetova, V V; Berestovitskaya, V M; Vasil'eva, O S

    2016-02-01

    GABA analogs containing phenyl (phenibut) or para-chlorophenyl (baclofen) substituents demonstrated nootropic activity in a dose of 20 mg/kg: they improved passive avoidance conditioning, decelerated its natural extinction, and exerted antiamnestic effect on the models of amnesia provoked by scopolamine or electroshock. Tolyl-containing GABA analog (tolibut, 20 mg/kg) exhibited antiamnestic activity only on the model of electroshock-induced amnesia. Baclofen and, to a lesser extent, tolibut alleviated seizures provoked by electroshock, i.e. both agents exerted anticonvulsant effect. All examined GABA aryl derivatives demonstrated neuroprotective properties on the maximum electroshock model: they shortened the duration of coma and shortened the period of spontaneous motor activity recovery. In addition, these agents decreased the severity of passive avoidance amnesia and behavioral deficit in the open field test in rats exposed to electroshock. The greatest neuroprotective properties were exhibited by phenyl-containing GABA analog phenibut.

  20. The central amygdala nucleus is critical for incubation of methamphetamine craving.

    Science.gov (United States)

    Li, Xuan; Zeric, Tamara; Kambhampati, Sarita; Bossert, Jennifer M; Shaham, Yavin

    2015-04-01

    Cue-induced methamphetamine seeking progressively increases after withdrawal but mechanisms underlying this 'incubation of methamphetamine craving' are unknown. Here we studied the role of central amygdala (CeA), ventral medial prefrontal cortex (vmPFC), and orbitofrontal cortex (OFC), brain regions implicated in incubation of cocaine and heroin craving, in incubation of methamphetamine craving. We also assessed the role of basolateral amygdala (BLA) and dorsal medial prefrontal cortex (dmPFC). We trained rats to self-administer methamphetamine (10 days; 9 h/day, 0.1 mg/kg/infusion) and tested them for cue-induced methamphetamine seeking under extinction conditions during early (2 days) or late (4-5 weeks) withdrawal. We first confirmed that 'incubation of methamphetamine craving' occurs under our experimental conditions. Next, we assessed the effect of reversible inactivation of CeA or BLA by GABAA+GABAB receptor agonists (muscimol+baclofen, 0.03+0.3 nmol) on cue-induced methamphetamine seeking during early and late withdrawal. We also assessed the effect of muscimol+baclofen reversible inactivation of vmPFC, dmPFC, and OFC on 'incubated' cue-induced methamphetamine seeking during late withdrawal. Lever presses in the cue-induced methamphetamine extinction tests were higher during late withdrawal than during early withdrawal (incubation of methamphetamine craving). Muscimol+baclofen injections into CeA but not BLA decreased cue-induced methamphetamine seeking during late but not early withdrawal. Muscimol+baclofen injections into dmPFC, vmPFC, or OFC during late withdrawal had no effect on incubated cue-induced methamphetamine seeking. Together with previous studies, results indicate that the CeA has a critical role in incubation of both drug and non-drug reward craving and demonstrate an unexpected dissociation in mechanisms of incubation of methamphetamine vs cocaine craving.

  1. G(o) transduces GABAB-receptor modulation of N-type calcium channels in cultured dorsal root ganglion neurons.

    Science.gov (United States)

    Menon-Johansson, A S; Berrow, N; Dolphin, A C

    1993-11-01

    High-voltage-activated (HVA) calcium channel currents (IBa) were recorded from acutely replated cultured dorsal root ganglion (DRG) neurons. IBa was irreversibly inhibited by 56.9 +/- 2.7% by 1 microM omega-conotoxin-GVIA (omega-CTx-GVIA), whereas the 1,4-dihydropyridine antagonist nicardipine was ineffective. The selective gamma-aminobutyric acidB (GABAB) agonist, (-)-baclofen (50 microM), inhibited the HVA IBa by 30.7 +/- 5.4%. Prior application of omega-CTx-GVIA completely occluded inhibition of the HVA IBa by (-)-baclofen, indicating that in this preparation (-)-baclofen inhibits N-type current. To investigate which G protein subtype was involved, cells were replated in the presence of anti-G protein antisera. Under these conditions the antibodies were shown to enter the cells through transient pores created during the replating procedure. Replating DRGs in the presence of anti-G(o) antiserum, raised against the C-terminal decapeptide of the G alpha o subunit, reduced (-)-baclofen inhibition of the HVA IBa, whereas replating DRGs in the presence of the anti-Gi antiserum did not. Using anti-G alpha o antisera (1:2000) and confocal laser microscopy, G alpha o localisation was investigated in both unreplated and replated neurons. G alpha o immunoreactivity was observed at the plasma membrane, neurites, attachment plaques and perinuclear region, and was particularly pronounced at points of cell-to-cell contact. The plasma membrane G alpha o immunoreactivity was completely blocked by preincubation with the immunising G alpha o undecapeptide (1 microgram.ml-1) for 1 h at 37 degrees C. A similar treatment also blocked recognition of G alpha o in brain membranes on immunoblots.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Highly Regioselective Palladium-Catalyzed Carboxylation of Allylic Alcohols with CO2.

    Science.gov (United States)

    Mita, Tsuyoshi; Higuchi, Yuki; Sato, Yoshihiro

    2015-11-01

    Various allylic alcohols were carboxylated in the presence of a catalytic amount of PdCl2 and PPh3 using ZnEt2 as a stoichiometric transmetalation agent under a CO2 atmosphere (1 atm). This carboxylation proceeded in a highly regioselective manner to afford branched carboxylic acids predominantly. The β,γ-unsaturated carboxylic acid thus obtained was successfully converted into an optically active γ-butyrolactone, a known intermediate of (R)-baclofen.

  3. [Clinical features of spastic dysphonia].

    Science.gov (United States)

    Vasilenko, Iu S; Golubev, V L; Debrianskaia, M B

    1995-01-01

    Clinical, neurological, endoscopic, psychological findings, questionnaire data on vegetative sphere, diaphragm x-ray, articulation test and Viene test system evidence obtained on 25 patients with phonic spasm confirm organic neurological nature of spastic dysphonia as focal muscular dystonia. This condition can be accompanied with tremor, rotatory, winking and writers' spasms, oromandibular dystonia. As indicated by positive treatment outcomes, combined treatment of phonic spasm with GABA-ergic drugs of clonazepam (antelepsin) and baclofen, orthophonic voice correction, physiotherapy is pathogenetically justified.

  4. Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

    Directory of Open Access Journals (Sweden)

    Riccardo Porta

    2016-12-01

    Full Text Available The metal-free reduction of nitro compounds to amines mediated by trichlorosilane was successfully performed for the first time under continuous-flow conditions. Aromatic as well as aliphatic nitro derivatives were converted to the corresponding primary amines in high yields and very short reaction times with no need for purification. The methodology was also extended to the synthesis of two synthetically relevant intermediates (precursors of baclofen and boscalid.

  5. Actions of 4-amino-3-(5-methoxybenzo(b)furan-2-yl) butanoic acid and 4-amino-3-benzo(b)furan-2-yl butanoic acid in the rat spinal cord.

    Science.gov (United States)

    Hammond, D L; Moy, M L

    1992-12-15

    This study examined whether two putative GABAB receptor antagonists, 4-amino-3-(5-methoxybenzo (b)furan-2-yl) butanoic acid (MBFG) and 4-amino-3-benzo(b)furan-2-yl butanoic acid (BFG), antagonized the antinociception produced by intrathecal (i.t) administration of the GABAB receptor agonist baclofen in the rat. In rats pretreated with 30 micrograms i.t. MBFG, the dose-effect relationship of D,L-baclofen was shifted approximately 2-fold and 4-fold to the right in the tail flick and hot plate tests, respectively. No further shift was obtained in the presence of 60 micrograms i.t. MBFG. I.t. injection of MBFG by itself did not alter either tail flick or hot plate latency. These data suggest that MBFG is a GABAB receptor antagonist in the spinal cord in vivo, although of marginal utility. Contrary to expectations, i.t. administration of 30-60 micrograms BFG alone increased tail flick and hot plate latencies; this increase was partially attenuated by coadministration of the GABAB receptor antagonist phaclofen. Pretreatment with 10 micrograms i.t. BFG, which was itself without effect on nociceptive threshold, antagonized the antinociceptive effects of 0.3 microgram i.t. L-baclofen, but interacted with higher and lower doses of baclofen in a complex manner. These results suggest that BFG acts as weak, partial agonist at GABAB receptors and that it may have additional, non-specific effects in the spinal cord of the rat. The pharmacological properties of BFG, therefore, resemble those of the GABAB receptor partial agonist/antagonist beta-phenyl-GABA, to which it bears a strong structural resemblance.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. GABA(B) receptor activation in the ventral tegmental area inhibits the acquisition and expression of opiate-induced motor sensitization.

    Science.gov (United States)

    Leite-Morris, Kimberly A; Fukudome, Eugene Y; Shoeb, Marwa H; Kaplan, Gary B

    2004-02-01

    Opiate-induced motor sensitization refers to the progressive and enduring motor response that develops after intermittent drug administration, and results from neuroadaptive changes in ventral tegmental area (VTA) and nucleus accumbens (NAc) neurons. Repeated activation of mu-opioid receptors localized on gamma-aminobutyric acid (GABA) neurons in the VTA enhances dopaminergic cell activity and stimulates dopamine release in the nucleus accumbens. We hypothesize that GABA(B) receptor agonist treatment in the VTA blocks morphine-induced motor stimulation, motor sensitization, and accumbal Fos immunoreactivity by inhibiting the activation of dopaminergic neurons. First, C57BL/6 mice were coadministered a single subcutaneous injection of morphine with intra-VTA baclofen, a GABA(B) receptor agonist. Baclofen produced a dose-dependent inhibition of opiate-induced motor stimulation that was attenuated by 2-hydroxysaclofen, a GABA(B) receptor antagonist. Next, morphine was administered on days 1, 3, 5, and 9 and mice demonstrated sensitization to its motor stimulant effects and concomitant induction of Fos immunoreactivity in the NAc shell (NAcS) but not NAc core. Intra-VTA baclofen administered during morphine pretreatment blocked the acquisition of morphine-induced motor sensitization and Fos activation in the NAcS. Intra-VTA baclofen administered only on day 9 blocked the expression of morphine-induced motor sensitization and Fos activation in the NAcS. A linear relationship was found between morphine-induced motor activity and accumbal Fos in single- and repeated-dose treatment groups. In conclusion, GABA(B) receptor stimulation in the VTA blocked opiate-induced motor stimulation and motor sensitization by inhibiting the activation of NAcS neurons. GABA(B) receptor agonists may be useful pharmacological treatments in altering the behavioral effects of opiates.

  7. STUDY OF ANTIDEPRESSANT LIKE EFFECT OF CORIANDRUM SATIVUM AND INVOLVEMENT OF MONOAMINONERGIC AND GABANERGIC SYSTEM

    OpenAIRE

    Naikwade Nilofer; Gumate Deepak; Kokane Sushant; Patil Vipul; Kharade Sudha

    2011-01-01

    The aim of this study was to examine possible mechanism of action of aqueous extract of Coriandrum sativum seed central nervous system of mice. We investigated the antidepressant-like mechanism of Coriandrum sativum by the combination of the Sulpiride (a selective dopamine D2 receptor antagonist), Prazosin (a α1 adrenoceptor antagonist), and Baclofen (GABA agonist). The results show that Coriandrum sativum (200 mg/kg, 400mg/kg, p.o.), significantly reduced the immobility time during Tail Susp...

  8. Behavioral analyses of GHB: receptor mechanisms.

    Science.gov (United States)

    Carter, Lawrence P; Koek, Wouter; France, Charles P

    2009-01-01

    GHB is used therapeutically and recreationally, although the precise mechanism of action responsible for its different behavioral effects is not entirely clear. The purpose of this review is to summarize how behavioral procedures, especially drug discrimination procedures, have been used to study the mechanism of action of GHB. More specifically, we will review several different drug discrimination procedures and discuss how they have been used to qualitatively and quantitatively study different components of the complex mechanism of action of GHB. A growing number of studies have provided evidence that the behavioral effects of GHB are mediated predominantly by GABAB receptors. However, there is also evidence that the mechanisms mediating the effects of GHB and the prototypical GABAB receptor agonist baclofen are not identical, and that other mechanisms such as GHB receptors and subtypes of GABAA and GABAB receptors might contribute to the effects of GHB. These findings are consistent with the different behavioral profile, abuse liability, and therapeutic indications of GHB and baclofen. A better understanding of the similarities and differences between GHB and baclofen, as well as the pharmacological mechanisms of action underlying the recreational and therapeutic effects of GHB, could lead to more effective medications with fewer adverse effects.

  9. Tonic activation of presynaptic GABAB receptors on rat pallidosubthalamic terminals

    Institute of Scientific and Technical Information of China (English)

    Lei CHEN; Wing-ho YUNG

    2005-01-01

    Aim: The subthalamic nucleus plays a critical role in the regulation of movement,and abnormal activity of its neurons is associated with some basal ganglia motor symptoms. We examined the presence of functional presynaptic GABAB receptors on pallidosubthalamic terminals and tested whether they were tonically active in the in vitro subthalamic slices. Methods: Whole-cell patch-clamp recordings were applied to acutely prepared rat subthalamic nucleus slices. The effects of specific GABAB agonist and antagonist on action potential-independent inhibitory postsynapfic currents (IPSCs), as well as holding current, were examined.Results: Superfusion of baclofen, a GABAB receptor agonist, significantly reduced the frequency of GABAA receptor-mediated miniature IPSCs (mIPSCs), in a Cd2+-sensitive manner, with no effect on the amplitude, indicating presynaptic inhibition on GABA release. In addition, baclofen induced a weak outward current only in a minority of subthalamic neurons. Both the pre- and post-synaptic effects of baclofen were prevented by the specific GABAB receptor antagonist,CGP55845. Furthermore, CGP55845 alone increased the frequency of mIPSCs,but had no effect on the holding current. Conclusion: These findings suggest the functional dominance of presynaptic GABAB receptors on the pallidosubthalamic terminals over the postsynaptic GABAB receptors on subthalamic neurons.Furthermore, the presynaptic, but not the postsynaptic, GABAB receptors are tonically active, suggesting that the presynaptic GABAB receptors in the subthalamic nucleus are potential therapeutic target for the treatment of Parkinson disease.

  10. Lack of effects of GHB precursors GBL and 1,4-BD following i.c.v. administration in rats.

    Science.gov (United States)

    Carter, Lawrence P; Koek, Wouter; France, Charles P

    2006-11-01

    Gamma-hydroxybutyrate (GHB) is used therapeutically and recreationally worldwide. Since the scheduling of GHB by the USA and the United Nations in 2000-2001, the recreational use of GHB precursors has reportedly increased. The aim of this study was to examine if potency differences of GHB and GHB-like compounds are due to their blood-brain barrier permeability. The effects of peripheral and central administration of GHB, GHB precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), and the gamma-aminobutyric acid (GABA)(B) receptor agonist baclofen on schedule-controlled responding were examined in rats. GHB and baclofen were 276- and 253-fold more potent, respectively, after intracerebroventricular (i.c.v.) administration than after intraperitoneal (i.p.) administration, whereas GBL and 1,4-BD, up to a dose of 1780 microg were without effect after i.c.v. administration. These data suggest that GBL and 1,4-BD are not metabolically converted to GHB in the brain, that enhanced brain penetration cannot account for potency differences between compounds, and that baclofen, like GHB, can readily cross the blood-brain barrier.

  11. Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current.

    Science.gov (United States)

    Best, Tyler K; Siarey, Richard J; Galdzicki, Zygmunt

    2007-01-01

    Down syndrome (DS) is the most common nonheritable cause of mental retardation. DS is the result of the presence of an extra chromosome 21 and its phenotype may be a consequence of overexpressed genes from that chromosome. One such gene is Kcnj6/Girk2, which encodes the G-protein-coupled inward rectifying potassium channel subunit 2 (GIRK2). We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus. Here we report that this overexpression leads to a significant increase ( approximately 2-fold) in GABA(B)-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady-state GIRK current density is significantly shifted left toward lower concentrations of baclofen in Ts65Dn neurons compared with diploid controls, consistent with increased functional expression of GIRK channels. Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single-channel conductance compared with diploid. However, significant increases in GIRK channel density was found in Ts65Dn neurons. In normalized baclofen-induced GIRK current and GIRK current kinetics no difference was found between diploid and Ts65Dn neurons, which suggests unimpaired mechanisms of interaction between GIRK channel and GABA(B) receptor. These results indicate that increased expression of GIRK2 containing channels have functional consequences that likely affect the balance between excitatory and inhibitory neuronal transmission.

  12. Determination of therapeutic γ-aminobutyric acid analogs in forensic whole blood by hydrophilic interaction liquid chromatography-electrospray tandem mass spectrometry.

    Science.gov (United States)

    Sørensen, Lambert K; Hasselstrøm, Jørgen B

    2014-05-01

    Vigabatrin, pregabalin, gabapentin and baclofen are γ-aminobutyric acid analogs that are used in the treatment of epileptic seizures (vigabatrin, pregabalin and gabapentin) and spasticity (baclofen). The intake of these drugs may induce adverse reactions and impair the ability of an individual to drive a vehicle. There have also been reports of cases of intoxication and fatalities from overdoses. For rapid and accurate quantification of these drugs in forensic cases, an ultraperformance liquid chromatography tandem mass spectrometry method using pneumatically assisted electrospray ionization has been developed. The technique has been validated on both ante- and postmortem human whole blood. The protein in the blood samples was removed by the addition of a mixture of methanol and acetonitrile, and the extract was ultrafiltered and diluted with acetonitrile. The separation was performed by hydrophilic interaction liquid chromatography. Calibration of the system was achieved through use of matrix-matched calibrants combined with isotope dilution. The lower limits of quantification were 0.02-0.04 mg/L, and the relative intra-laboratory reproducibility standard deviations were 89%. The trueness expressed as the relative bias of the test results was within ±7% at concentrations of 1-40 mg/L for vigabatrin, pregabalin and gabapentin and of 0.1-4 mg/L for baclofen.

  13. STUDY OF ANTIDEPRESSANT LIKE EFFECT OF CORIANDRUM SATIVUM AND INVOLVEMENT OF MONOAMINONERGIC AND GABANERGIC SYSTEM

    Directory of Open Access Journals (Sweden)

    Naikwade Nilofer

    2011-02-01

    Full Text Available The aim of this study was to examine possible mechanism of action of aqueous extract of Coriandrum sativum seed central nervous system of mice. We investigated the antidepressant-like mechanism of Coriandrum sativum by the combination of the Sulpiride (a selective dopamine D2 receptor antagonist, Prazosin (a α1 adrenoceptor antagonist, and Baclofen (GABA agonist. The results show that Coriandrum sativum (200 mg/kg, 400mg/kg, p.o., significantly reduced the immobility time during Tail Suspension Test (TST. We also investigated the antidepressant-like mechanism of Coriandrum sativum by the combination of Sulpiride (a selective dopamine D2 receptor antagonist, Prazosin (a α1 adrenoceptor antagonist, and Baclofen (GABA agonist. The immobility time after treatment with Coriandrum sativum (200 mg/kg, 400mg/kg, p.o. in TST was augmented by Sulpiride, Baclofen, Prazosin. Our findings support the view that Coriandrum sativum exerts antidepressant-like effect. And the mechanism of action of Coriandrum sativum may be related to the increase in Nor adrenaline and serotonin levels in the hippocampus and frontal cortex.

  14. Does pain relief influence recovery of consciousness? A case report of a patient treated with ziconotide.

    Science.gov (United States)

    Lanzillo, Bernardo; Loreto, Vincenzo; Calabrese, Claudio; Estraneo, Anna; Moretta, Pasquale; Trojano, Luigi

    2016-04-01

    For people with cervical spinal cord injury (SCI), access to computers can be difficult, thus several devices have been developed to facilitate their Disorders of consciousness (DOC) are difficult to classify. The degree of consciousness varies from coma to vegetative state or unresponsive wakefulness syndrome (UWS) and minimally conscious state. Correct diagnosis has important ethical and legal implications, and pain may be cause of misdiagnosis. We describe here a patient with traumatic brain injury, classified as UWS. His clinical picture was dominated by spasticity, and pain. He underwent intrathecal treatment of spasticity with baclofen. Improvement was not that expected. However, there was a dramatic improvement when ziconotide was added to relieve pain; the patient began to eat by mouth, talk, and his tracheal tube could be removed and he is currently classified as having severe disability. The suspension of ziconotide caused a clear re-worsening of clinical condition, reverted by his reintroduction. Pain is an important factor in patients with DOC. Anecdotal reports of improved consciousness with intrathecal baclofen therapy may be due to pain relief. Reduction of pain in DOC is important and drugs should not interfere with cognition, and must be effective and manageable. Ziconotide may be one of the possible candidate due to its synergistic antispastic action in combination with baclofen when an intratecal pump has been implanted.

  15. Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability.

    Science.gov (United States)

    Fairfax, Benjamin P; Pitcher, Julie A; Scott, Mark G H; Calver, Andrew R; Pangalos, Menelas N; Moss, Stephen J; Couve, Andrés

    2004-03-26

    GABA(B) receptors are heterodimeric G protein-coupled receptors that mediate slow synaptic inhibition in the central nervous system. The dynamic control of the cell surface stability of GABA(B) receptors is likely to be of fundamental importance in the modulation of receptor signaling. Presently, however, this process is poorly understood. Here we demonstrate that GABA(B) receptors are remarkably stable at the plasma membrane showing little basal endocytosis in cultured cortical and hippocampal neurons. In addition, we show that exposure to baclofen, a well characterized GABA(B) receptor agonist, fails to enhance GABA(B) receptor endocytosis. Lack of receptor internalization in neurons correlates with an absence of agonist-induced phosphorylation and lack of arrestin recruitment in heterologous systems. We also demonstrate that chronic exposure to baclofen selectively promotes endocytosis-independent GABA(B) receptor degradation. The effect of baclofen can be attenuated by activation of cAMP-dependent protein kinase or co-stimulation of beta-adrenergic receptors. Furthermore, we show that increased degradation rates are correlated with reduced receptor phosphorylation at serine 892 in GABA(B)R2. Our results support a model in which GABA(B)R2 phosphorylation specifically stabilizes surface GABA(B) receptors in neurons. We propose that signaling pathways that regulate cAMP levels in neurons may have profound effects on the tonic synaptic inhibition by modulating the availability of GABA(B) receptors.

  16. Initial characterization of receptors for molecules that induce the settlement and metamorphosis of Haliotis rufescens larvae

    Energy Technology Data Exchange (ETDEWEB)

    Trapido-Rosenthal, H.G.

    1985-01-01

    Larvae of the marine gastropod mollusc Haliotis refescens are induced to undergo metamorphosis by ..gamma..-aminobutyric acid (GABA) and stereochemically related compounds. The most potent of these inducers is (-)-..beta..-(parachlorophenyl)-GABA (baclofen). The inductive response exhibits positive cooperatively, and is subject to both facilitation (up-regulation) and habituation (down-regulation). Facilitation is brought about by diamino acids such as L-diaminopropionic acid (L-DAPA), and is characterized by decreased Hill coefficients (n/sub H/) and concentration requirements (EC/sub 50/) for inducers. Facilitation does not require the simultaneous presence of facilitating and inducing compounds, and the facilitated state is persistent. Larvae are capable of being up-regulated 2 days before they are capable of undergoing settlement and metamorphosis. Habituation can be brought about by exposure of pre-competent larvae to GABA 4 days prior to the attainment of competence; it is then slowly reversible. Larvae specifically bind tritiated (-)-baclofen in a manner that is saturable with both increasing time of exposure of larvae to, and with increasing concentration of, this compound. Specific binding can be competed for by unlabeled GABA-mimetic inducing molecules; the order of effectiveness of these molecules as competitors for specific binding correlates well with their effectiveness as inducers of metamorphosis. Facilitation of larvae by exposure to diamino acids does not alter their specific binding of tritiated (-)-baclofen. It is concluded from these findings that Haliotis larvae possess receptors for GABA-mimetic compounds.

  17. Differential involvement of GABAA and GABAB receptors in propofol self-administration in rats

    Institute of Scientific and Technical Information of China (English)

    Bo YANG; Ben-fu WANG; Miao-jun LAI; Fu-qiang ZHANG; Xiao-wei YANG; Wen-hua ZHOU; Qing-quan LIAN

    2011-01-01

    Propofol has shown abuse potential.The aim of the present study is to investigate the effects of GABAA antagonist and GABAB agonist on propofol reinforcement.Methods:Sprague-Dawley rats were trained to self-administer propofol at a dose of 1.7 mg/kg per infusion under a fixed ratio (FR1) schedule of reinforcement for 14 d.In a separate set of experiments,food-maintained self-administration under a fixed ratio (FR5) schedule and locomotor activities of Sprague-Dawley rats were examined.Results:GABAA receptor antagonist bicuculline (0.25 mg/kg,ip) significantly increased the number of injections and active responses.Pretreatment with GABAB receptor agonist baclofen (3 mg/kg,ip) significantly decreased the number of active responses and total infusions of propofol during the training session.Moreover,microinjection of baclofen (50 and 100 ng/side) into the ventral tegmental area (VTA) significantly decreased the number of active responses and total infusions of propofol.Neither baclofen (1-3 mg/kg,ip) nor bicuculline (0.25-1 mg/kg,ip) affected food-maintained responses or motor activities.Conclusion:Propofol maintains its reward properties partially through GABAA receptor activation.Stimulation of GABA~ receptors in VTA may counteract the reinforcing properties of propofol.

  18. Walking with Neuropathic Pain: Paradoxical Shift from Burden to Support?

    Directory of Open Access Journals (Sweden)

    David J. Kopsky

    2015-01-01

    Full Text Available Baclofen 5% cream can be used for the treatment of neuropathic pain. We describe an unusual case of a neuropathic pain patient with spinal cord injury. A 71-year-old woman with a partial spinal cord injury lesion at L4 complained of tingling, pins and needles, and burning in her legs. She scored her pain as 6 before adding baclofen 5% cream to her pain medication (pregabalin 450 mg, acetaminophen 3000 mg, and diclofenac 150 mg daily. One month later she experienced complete pain relief, though experienced increased difficulties in walking, leading to frequent falls. Her steadier walking without stumbling and falling was more important to her than pain reduction. Thus she decided to stop using baclofen. This unusual case report discusses two important issues that relate to pain medicine and rehabilitation in patients with painful spinal cord lesions: (1 the presence of wide areas of sensory loss “covered” by the presence of painful sensations and (2 pathological sensations that can be used and integrated in the body schema to create an improved spatiovisual orientation and thus mobility. Both these aspects have to be taken into account when treating pain and design rehabilitation programs.

  19. Differential drug effects on spontaneous and evoked pain behavior in a model of trigeminal neuropathic pain

    Science.gov (United States)

    Deseure, K; Hans, GH

    2017-01-01

    Purpose Baclofen and morphine have shown efficacy against mechanical allodynia after infraorbital nerve chronic constriction injury (IoN-CCI). No drug effects have yet been reported on spontaneous trigeminal neuropathic pain. It has been proposed that the directed face grooming behavior that also develops following IoN-CCI offers a measure of spontaneous trigeminal neuropathic pain. Subjects and methods We examined the effects of a continuous 1-week infusion of 30 mg/day carbamazepine (the first-line drug treatment for trigeminal neuralgia), 1.06 mg/day baclofen, 4.18 mg/day clomipramine, and 5 mg/day morphine on spontaneous and mechanically evoked pain behavior (ie, directed face grooming and von Frey testing) in IoN-CCI rats. Results Isolated face grooming was significantly reduced in rats receiving carbamazepine and baclofen but not in clomipramine- or morphine-treated rats. All drugs showed significant antiallodynic effects; carbamazepine showed the strongest effects, whereas clomipramine had only minor efficacy. Conclusion The tested drugs have differential effects in the IoN-CCI model, and different neuropathological mechanisms may underlie the different somatosensory symptoms in this model. A mechanism-based approach may be needed to treat (trigeminal) neuropathic pain. The present data support IoN-CCI as a model of trigeminal neuralgia in which isolated face grooming is used as a measure of spontaneous neuropathic pain. PMID:28184169

  20. Trigemino-cervical reflex in spinal cord injury.

    Science.gov (United States)

    Gündüz, Ayşegül; Uzun, Nurten; Örnek, Nurettin İrem; Ünalan, Halil; Karamehmetoğlu, Şafak Sahir; Kızıltan, Meral E

    2014-09-19

    Abnormal enhancement of polysynaptic brainstem reflexes has been previously reported in patients with spinal cord injury (SCI). We aimed to investigate trigemino-cervical reflex (TCR) in SCI since it may reflect alterations in the connections of trigeminal proprioceptive system and cervical motoneurons. Consecutive 14 patients with SCI and 16 healthy subjects were included in this study. All patients were in the chronic phase. TCR was recorded over sternocleidomastoid (SCM) and splenius capitis (SC) muscles by stimulation of infraorbital nerve. We measured onset latency, amplitudes and durations of responses and compared between groups. We obtained stable responses over both muscles after one sided stimulation in healthy volunteers whereas probability of TCR was decreased in patients over both SCM (78.6% vs. 100%, p=0.050) and SC (71.4% vs. 100%, p=0.022). The absence of TCR was related to use of oral baclofen (≥50mg/day). However, when present, responses of SCI group had higher amplitudes and were more persistent. We demonstrated that TCR probability was similar to healthy subjects in SCI patients who used no or low dose oral baclofen. But it had higher amplitudes and longer durations. It was not obtained in only two patients who used oral baclofen more than 50mg/day.

  1. γ-Aminobutyric Acid B Receptor Mediated Inhibition of Gonadotropin-Releasing Hormone Neurons Is Suppressed by Kisspeptin-G Protein-Coupled Receptor 54 Signaling

    Science.gov (United States)

    Zhang, Chunguang; Bosch, Martha A.; Rønnekleiv, Oline K.; Kelly, Martin J.

    2009-01-01

    γ-Aminobutyric acid (GABA) is one of the most important neurotransmitters that regulate the excitability of GnRH neurons. Numerous studies have shown that GABA activates Cl− currents in GnRH neurons, and these effects are antagonized by GABAA receptor antagonists. The GABAB receptor is a heterodimer composed of GABAB R1 and R2, and although both subunits have been localized in GnRH neurons, nothing is known about the cellular signaling of this Gαi,o-coupled receptor in GnRH neurons. Using whole-cell recordings from mouse enhanced green fluorescent protein-GnRH neurons, we found that the GABAB receptor agonist baclofen hyperpolarized GnRH neurons through activation of an inwardly rectifying K+ current in a concentration-dependent manner. The effects of baclofen were antagonized by the selective GABAB receptor antagonist CGP 52432 with a Ki (inhibitory constant) of 85 nm. Furthermore, in the presence of the GABAA receptor antagonist picrotoxin, GABA hyperpolarized GnRH neurons in a similar manner. Treatment with 17β-estradiol as compared with oil vehicle did not significantly alter either the EC50 for the baclofen-induced response (0.8 ± 0.1 vs. 1.0 ± 0.1 μm, respectively) or the maximal outward current (10.8 ± 1.7 pA vs. 11.4 ± 0.6 pA, respectively) in GnRH neurons. However, the outward current (and membrane hyperpolarization) was abrogated by submaximal concentrations of the G protein-coupled receptor 54 (GPR54) agonist kisspeptin-10 in both groups, indicating that Gαq-coupled (GPR54) can desensitize the GABAB receptor-mediated response. Therefore, the activation of GABAB receptors in GnRH neurons may provide increased inhibitory tone during estrogen-negative feedback states that is attenuated by kisspeptin during positive feedback. PMID:19164470

  2. Opioid and GABAB receptors differentially couple to an adenylyl cyclase/protein kinase A downstream effector after chronic morphine treatment.

    Directory of Open Access Journals (Sweden)

    Elena Elizabeth Bagley

    2014-06-01

    Full Text Available Opioids are intensely addictive, and cessation of their chronic use is associated with a highly aversive withdrawal syndrome. A cellular hallmark of withdrawal is an opioid sensitive protein kinase A-dependent increase in GABA transporter-1 (GAT-1 currents in periaqueductal gray (PAG neurons. Elevated GAT-1 activity directly increases GABAergic neuronal excitability and synaptic GABA release, which will enhance GABAergic inhibition of PAG output neurons. This reduced activity of PAG output neurons to several brain regions, including the hypothalamus and medulla, contributes to many of the PAG-mediated signs of opioid withdrawal. The GABAB receptor agonist baclofen reduces some of the PAG mediated signs of opioid withdrawal. Like the opioid receptors the GABAB receptor is a Gi/Go coupled G-protein coupled receptor. This suggests it could be modulating GAT-1 activity in PAG neurons through its inhibition of the adenylyl cyclase/protein kinase A pathway. Opioid modulation of the GAT-1 activity can be detected by changes in the reversal potential of opioid membrane currents. We found that when opioids are reducing the GAT-1 cation conductance and increasing the GIRK conductance the opioid agonist reversal potential is much more negative than Ek. Using this approach for GABAB receptors we show that the GABAB receptor agonist, baclofen, does not couple to inhibition of GAT-1 currents during opioid withdrawal. It is possible this differential signaling of the two Gi/Go coupled G-protein coupled receptors is due to the strong compartmentalization of the GABAB receptor that does not favor signaling to the adenylyl cyclase/protein kinase A/GAT-1 pathway. This highlights the importance of studying the effects of G-protein coupled receptors in native tissue with endogenous G-protein coupled receptors and the full complement of relevant proteins and signaling molecules. This study suggests that baclofen reduces opioid withdrawal symptoms through a non-GAT-1

  3. The bradycardic and hypotensive responses to serotonin are reduced by activation of GABA A receptors in the nucleus tractus solitarius of awake rats

    Directory of Open Access Journals (Sweden)

    J.C. Callera

    2005-07-01

    Full Text Available We investigated the effects of bilateral injections of the GABA receptor agonists muscimol (GABA A and baclofen (GABA B into the nucleus tractus solitarius (NTS on the bradycardia and hypotension induced by iv serotonin injections (5-HT, 2 µg/rat in awake male Holtzman rats. 5-HT was injected in rats with stainless steel cannulas implanted bilaterally in the NTS, before and 5, 15, and 60 min after bilateral injections of muscimol or baclofen into the NTS. The responses to 5-HT were tested before and after the injection of atropine methyl bromide. Muscimol (50 pmol/50 nl, N = 8 into the NTS increased basal mean arterial pressure (MAP from 115 ± 4 to 144 ± 6 mmHg, did not change basal heart rate (HR and reduced the bradycardia (-40 ± 14 and -73 ± 26 bpm at 5 and 15 min, respectively, vs -180 ± 20 bpm for the control and hypotension (-11 ± 4 and -14 ± 4 mmHg, vs -40 ± 9 mmHg for the control elicited by 5-HT. Baclofen (12.5 pmol/50 nl, N = 7 into the NTS also increased basal MAP, but did not change basal HR, bradycardia or hypotension in response to 5-HT injections. Atropine methyl bromide (1 mg/kg body weight injected iv reduced the bradycardic and hypotensive responses to 5-HT injections. The stimulation of GABA A receptors in the NTS of awake rats elicits a significant increase in basal MAP and decreases the cardiac Bezold-Jarisch reflex responses to iv 5-HT injections.

  4. Simultaneous stimulation of GABA and beta adrenergic receptors stabilizes isotypes of activated adenylyl cyclase heterocomplex

    Directory of Open Access Journals (Sweden)

    Robichon Alain

    2004-06-01

    Full Text Available Abstract Background We investigated how the synthesis of cAMP, stimulated by isoproterenol acting through β-adrenoreceptors and Gs, is strongly amplified by simultaneous incubation with baclofen. Baclofen is an agonist of δ-aminobutyric acid type B receptors [GABAB], known to inhibit adenylyl cyclase via Gi. Because these agents have opposite effects on cAMP levels, the unexpected increase in cAMP synthesis when they are applied simultaneously has been intensively investigated. From previous reports, it appears that cyclase type II contributes most significantly to this phenomenon. Results We found that simultaneous application of isoproterenol and baclofen specifically influences the association/dissociation of molecules involved in the induction and termination of cyclase activity. Beta/gamma from [GABA]B receptor-coupled Gi has a higher affinity for adenylyl cyclase isoform(s when these isoforms are co-associated with Gs. Our data also suggest that, when beta/gamma and Gαs are associated with adenylyl cyclase isoform(s, beta/gamma from [GABA]B receptor-coupled Gi retards the GTPase activity of Gαs from adrenergic receptor. These reciprocal regulations of subunits of the adenylyl cyclase complex might be responsible for the drastic increase of cAMP synthesis in response to the simultaneous signals. Conclusions Simultaneous signals arriving at a particular synapse converge on molecular detectors of coincidence and trigger specific biochemical events. We hypothesize that this phenomenon comes from the complex molecular architectures involved, including scaffolding proteins that make reciprocal interactions between associated molecules possible. The biochemistry of simultaneous signaling is addressed as a key to synaptic function.

  5. Medical treatment of nystagmus and ocular motor disorders.

    Science.gov (United States)

    Carlow, T J

    1986-01-01

    An increased compendium of drugs useful in ocular motor system dysfunction has expanded our capacity to treat selected ocular motility disorders. Adjunctive therapeutic modes (e.g., Fresnel prisms and orthoptic exercises) can also be beneficial. PAN and see-saw nystagmus can be treated with baclofen. Downbeat nystagmus may respond to clonazepam therapy, and prisms may help if the nystagmus can be modified with convergence. Congenital nystagmus may respond minimally to drugs (e.g., baclofen), but prisms or surgical procedures, or both, are still the primary treatment modalities. Innovar may be helpful in patients with severe, incapacitating vestibular disorders, and scopolamine alone or in combination with promethazine may be beneficial in patients with milder ambulatory acute peripheral vestibular disorders. Benign positional vertigo is best treated initially with positional exercises before drug therapy is instituted. Opsoclonus and ocular flutter have been treated successfully with corticosteroids, propranolol, and clonazepam, while microflutter, an extremely rare disorder, can resolve with baclofen. Although therapy with carbamazepine, 5-hydroxtryptophan, and scopolamine has been useful in selected patients with ocular palatal myoclonus, most do not respond to drug treatment. It is not usually necessary to treat voluntary nystagmus, but Fresnel prism lenses should be remembered in refractory patients. Potentially reversible and pseudointernuclear ophthalmoplegias also were discussed. Orthoptic exercises can be beneficial in posttraumatic internuclear ophthalmoplegia. Selected supranuclear palsies can be improved completely with the proper drug regimen. Lastly, superior oblique myokymia can be treated successfully with carbamazepine, with tight surveillance for possible adverse side effects. Descriptive phenomenology and pathophysiological localization must be correlated with brain stem neurochemistry and neuropharmacology to medically treat additional ocular

  6. Carisoprodol withdrawal syndrome resembling neuroleptic malignant syndrome: Diagnostic dilemma

    Directory of Open Access Journals (Sweden)

    Gunchan Paul

    2016-01-01

    Full Text Available Soma (Carisoprodol is N-isopropyl-2 methyl-2-propyl-1,3-propanediol dicarbamate; a commonly prescribed, centrally acting skeletal muscle relaxant. Neuroleptic malignant syndrome (NMS is a potentially life-threatening adverse effect of antipsychotic agents. Although diagnostic criteria for NMS have been established, it should be recognized that atypical presentations occur and more flexible diagnostic criteria than currently mandated, may be warranted. We wish to report a postoperative case of bilateral knee replacement who presented with carisoprodol (Soma withdrawal resembling NMS that was a diagnostic dilemma. Subsequently, it was successfully treated with oral baclofen in absence of sodium dantrolene.

  7. Carisoprodol withdrawal syndrome resembling neuroleptic malignant syndrome: Diagnostic dilemma

    Science.gov (United States)

    Paul, Gunchan; Parshotam, Gautam L; Garg, Rajneesh

    2016-01-01

    Soma (Carisoprodol) is N-isopropyl-2 methyl-2-propyl-1,3-propanediol dicarbamate; a commonly prescribed, centrally acting skeletal muscle relaxant. Neuroleptic malignant syndrome (NMS) is a potentially life-threatening adverse effect of antipsychotic agents. Although diagnostic criteria for NMS have been established, it should be recognized that atypical presentations occur and more flexible diagnostic criteria than currently mandated, may be warranted. We wish to report a postoperative case of bilateral knee replacement who presented with carisoprodol (Soma) withdrawal resembling NMS that was a diagnostic dilemma. Subsequently, it was successfully treated with oral baclofen in absence of sodium dantrolene. PMID:27625493

  8. Antagonism of GABAB-receptor-mediated responses in the guinea-pig isolated ileum and vas deferens by phosphono-analogues of GABA.

    OpenAIRE

    Kerr, D. I.; Ong, J; Prager, R. H.

    1990-01-01

    1. The phosphono-analogues of gamma-aminobutyric acid (GABA), 4-amino-butylphosphonic acid (4-ABPA), 3-amino-2-(4-chlorophenyl)-propylphosphonic acid (phaclofen) and 3-amino-2-cyclohexylpropyl-phosphonic acid, each antagonized the GABA- and baclofen-induced GABAB-receptor-mediated depression of twitch responses to transmural stimulation in the guinea-pig isolated ileum, in a concentration-dependent, reversible and surmountable manner (apparent pA2 = 4.0 +/- 0.1, 4 +/- 0.2 and 3.7 +/- 0.2 resp...

  9. [Chronic high frequency deep brain stimulation of the globus pallidus internus for torsion dystonia].

    Science.gov (United States)

    Vesper, J; Klostermann, F; Funk, T; Bock, M

    2002-01-01

    Deep Brain Stimulation (DBS, chronic high frequency stimulation) is well established for Parkinson's disease and tremordominant movement disorders. Generalized dystonia is known as a type of movement disorder in which therapeutic options are very limited. A case of generalized dystonia is reported which was successfully treated by DBS in the Globus pallidus internus (GPI). A 26 years old male suffered from severe torsion dystonia of the lower limbs. The onset of symptoms was at age 7. It started with dystonia of the left foot. He very fast developed severe dystonia of the lower limbs. These complaints were initially treated by diazepam, later by baclofen (Lioresal ((R))) p.o em leader There was no L-DOPA response. Because of the rapid progression of the disease a cervical spinal cord stimulator was implanted with a transient success. Due to further progression of the disease the patient became wheelchair bounded and resistant for oral medication. Limited improvement of symptoms was achieved using continuous intrathecal administration of baclofen. Finally the patient was treated with 980 microgram intrathecal Baclofen (Lioresal ((R))) daily and up to 100 mg diazepam. Under these conditions the patient remained wheelchair bounded with severe lower limb dystonia. As an ultima ratio it was decided to treat the patient with stereotactic implantation of two electrodes (Medtronic 3387) and two neurostimulators (Medtronic ITREL ((R))II). The GPI was the bilateral target point. Intraoperative computerized tomography and ventriculography were used for target setting. Furthermore microrecordings were helpful to ensure the exact electrode positioning. Surgery was performed under sedation. Two weeks after surgery first improvement of symptoms was observed. Patient was able to stand with assistance. At the three months follow-up he could walk without assistance. Slight dystonic movement of the left ankle was the only remaining symptom under stimulation. The oral medication has

  10. Glutamic acid decarboxylase antibody-positive paraneoplastic stiff limb syndrome associated with carcinoma of the breast

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    Agarwal Pankaj

    2010-01-01

    Full Text Available Stiff limb syndrome (SLS is a rare "focal" variant of stiff person syndrome which presents with rigidity and painful spasms of a distal limb, and abnormal fixed foot or hand postures. Anti-glutamic acid decarboxylase antibodies (GAD-Ab are variably present in most cases. Most reported cases of SLS are unassociated with cancer. We describe a patient with SLS as a paraneoplastic manifestation of breast carcinoma, in whom GAD-Ab was present. The patient responded very well to oral diazepam, baclofen and steroids.This is the third reported case of SLS as a paraneoplastic accompaniment to cancer.

  11. Glutamic acid decarboxylase antibody-positive paraneoplastic stiff limb syndrome associated with carcinoma of the breast.

    Science.gov (United States)

    Agarwal, Pankaj A; Ichaporia, Nasli R

    2010-01-01

    Stiff limb syndrome (SLS) is a rare "focal" variant of stiff person syndrome which presents with rigidity and painful spasms of a distal limb, and abnormal fixed foot or hand postures. Anti-glutamic acid decarboxylase antibodies (GAD-Ab) are variably present in most cases. Most reported cases of SLS are unassociated with cancer. We describe a patient with SLS as a paraneoplastic manifestation of breast carcinoma, in whom GAD-Ab was present. The patient responded very well to oral diazepam, baclofen and steroids.This is the third reported case of SLS as a paraneoplastic accompaniment to cancer.

  12. Paroxysmal Autonomic Instability with Dystonia after Pneumococcal Meningoencephalitis

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    Layal Safadieh

    2012-01-01

    Full Text Available Streptococcus pneumoniae is a common cause of bacterial meningitis, frequently resulting in severe neurological impairment. A seven-month-old child presenting with Streptococcus pneumoniae meningoencephalitis developed right basal ganglia and hypothalamic infarctions. Daily episodes of agitation, hypertension, tachycardia, diaphoresis, hyperthermia, and decerebrate posturing were observed. The diagnosis of paroxysmal autonomic instability with dystonia was established. The patient responded to clonidine, baclofen, and benzodiazepines. Although this entity has been reported in association with traumatic brain injury, and as a sequel to some nervous system infections, this is the first case, to our knowledge, associated with pneumococcal meningoencephalitis.

  13. FUNCTIONAL DYNAMICS OF PRIMATE CORTICO-STRIATAL NETWORKS DURING VOLITIONAL MOVEMENTS

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    Lucas M Santos

    2014-03-01

    Full Text Available The motor cortex and dorsal striatum (caudate nucleus and putamen are key regions in motor processing but the interface between the cortex and striatum is not well understood. While dorsal striatum integrates information from multiple brain regions to shape motor learning and habit formation, the disruption of cortico-striatal circuits compromises the functionality of these circuits resulting in a multitude of neurologic disorders, including Parkinson’s disease. To better understand the modulation of the cortico-striatal circuits we recorded simultaneously single neuron activity from four brain regions, primary motor and sensory cortices, together with the rostral and caudal segments of the putamen in rhesus monkeys performing a visual motor task. Results show that spatial and temporal-task related firing relationships between these cortico-striatal circuit regions were modified by the independent administration of the two drugs (cocaine and baclofen. Spatial tuning and correlated firing of neurons from motor cortex and putamen were severely disrupted by cocaine and baclofen on correct trials, while the two drugs have dramatically decreased the functional connectivity of the motor cortical-striatal network. These findings provide insight into the modulation of cortical-striatal firing related to movement with implications for therapeutic approaches to Parkinson’s disease and related disorders.

  14. New topical treatment of vulvodynia based on the pathogenetic role of cross talk between nociceptors, immunocompetent cells, and epithelial cells

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    Keppel Hesselink JM

    2016-10-01

    Full Text Available J M Keppel Hesselink,1 D J Kopsky,2 N Sajben3 1Institute for Neuropathic Pain, Bosch en Duin, 2Institute for Neuropathic Pain, Amsterdam, The Netherlands; 3Scripps Memorial Hospital La Jolla, La Jolla, CA, USA Abstract: Topical treatments of localized neuropathic pain syndromes in general are mostly neglected, mainly due to the fact that most pain physicians expect that a topical formulation needs to result in a transdermal delivery of the active compounds. On the basis of the practical experience, this study brings forth a new, somewhat neglected element of the vulvodynia pathogenesis: the cross talk between the nerve endings of nociceptors, the adjacent immunocompetent cells, and vaginal epithelial cells. Insight into this cross talk during a pathogenic condition supports the treatment of vulvodynia with topical (compounded creams. Vulvodynia was successfully treated with an analgesic cream consisting of baclofen 5% together with the autacoid palmitoylethanolamide 1%, an endogenous anti-inflammatory compound. In this review, data is presented to substantiate the rationale behind developing and prescribing topical products for localized pain states such as vulvodynia. Most chronic inflammatory disorders are based on a network pathogenesis, and monotherapeutic inroads into the treatment of such disorders are obsolete. Keywords: vulva, cream, autacoid, mast cell, pain, analgesia, pathogenesis, baclofen, palmitoylethanolamide

  15. The role of piriform associative connections in odor categorization.

    Science.gov (United States)

    Bao, Xiaojun; Raguet, Louise Lg; Cole, Sydni M; Howard, James D; Gottfried, Jay

    2016-04-28

    Distributed neural activity patterns are widely proposed to underlie object identification and categorization in the brain. In the olfactory domain, pattern-based representations of odor objects are encoded in piriform cortex. This region receives both afferent and associative inputs, though their relative contributions to odor perception are poorly understood. Here, we combined a placebo-controlled pharmacological fMRI paradigm with multivariate pattern analyses to test the role of associative connections in sustaining olfactory categorical representations. Administration of baclofen, a GABA(B) agonist known to attenuate piriform associative inputs, interfered with within-category pattern separation in piriform cortex, and the magnitude of this drug-induced change predicted perceptual alterations in fine-odor discrimination performance. Comparatively, baclofen reduced pattern separation between odor categories in orbitofrontal cortex, and impeded within-category generalization in hippocampus. Our findings suggest that odor categorization is a dynamic process concurrently engaging stimulus discrimination and generalization at different stages of olfactory information processing, and highlight the importance of associative networks in maintaining categorical boundaries.

  16. In vitro detection of oxygen and glucose deprivation-induced neurodegeneration and pharmacological neuroprotection based on hippocampal stratum pyramidale width.

    Science.gov (United States)

    Öz, Pınar; Saybaşılı, Hale

    2017-01-01

    Ischemia is one of the most prominent risk factors of neurodegenerative diseases such as Alzheimer's disease. The effects of oxygen and glucose depletion in hippocampal tissue due to ischemia can be mimicked in vitro using the oxygen and glucose deprivation (OGD) model. In this study, we applied OGD on acute rat hippocampal slices in order to design an elementary yet quantitative histological technique that compares the neuroprotective effects of (l)-carnitine to known neuroprotectors, such as the N-methyl-d-aspartate (NMDA) receptor antagonist memantine and the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen. The level of neurodegeneration and the efficiency of pharmacological applications were estimated via stratum pyramidale width measurements in CA1 and CA3 regions of Nissl-stained 200-μm thick hippocampal slices. We demonstrated that (l)-carnitine is an effective pharmacological target against the neurodegeneration induced by in vitro ischemia in a narrow range of concentrations. Even though the effect of chemical neuroprotection was significant, full recovery was not achieved in the dose interval of 5-100μM. In addition to chemical applications, hypothermia was used as a physical neuroprotection against ischemia-related neurodegeneration. Our results showed that incubation of slices for 60min at 4°C provided the same level of neuroprotection as the most effective doses of memantine, baclofen, and (l)-carnitine.

  17. An historical perspective on GABAergic drugs.

    Science.gov (United States)

    Froestl, Wolfgang

    2011-02-01

    In 1950, γ-aminobutyric acid (GABA) was discovered in the brain and in 1967 it was recognized as an inhibitory neurotransmitter. The discovery of the benzodiazepines Librium® (launched in 1960) and Valium® by Sternbach initiated huge research activities resulting in 50 marketed drugs. In 1975, Haefely found that GABA is involved in the actions of benzodiazepines. The baclofen-sensitive, bicuculline-insensitive GABA(B) receptor was discovered by Bowery in 1980, and the baclofen-insensitive, bicuculline-insensitive GABA(C) receptor by Johnston in 1984. Barnard & Seeburg reported the cloning of the GABA(A) receptor in 1987, Cutting the GABA(C) receptor in 1991 and Bettler the GABA(B1a) and GABA(B1b) receptors in 1997. Six groups cloned the GABA(B2) receptor in 1998/1999 showing that the GABA(B) receptor functions as a heterodimer with GABA(B1b)/GABA(B2) mediating postsynaptic inhibition and GABA(B1a)/GABA(B2) mediating presynaptic inhibition. Möhler and McKernan dissected the pharmacology of the benzodiazepine-receptor subtypes. Antagonists and positive allosteric modulators of GABA(B) receptors were discovered in 1987 and 2001, respectively. GABA transporter inhibitor, tiagabine, was launched in 1996, a GABA aminotransferase inhibitor, vigabatrin, in 1998 and a glutamic acid decarboxylase activator, pregabalin, in 2004. Most recently, brain-penetrating GABA(C)-receptor antagonists were reported in 2009.

  18. GABA in Paraventricular Nucleus Regulates Adipose Afferent Reflex in Rats.

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    Lei Ding

    Full Text Available Chemical stimulation of white adipose tissue (WAT induces adipose afferent reflex (AAR, and thereby causes a general sympathetic activation. Paraventricular nucleus (PVN is important in control of sympathetic outflow. This study was designed to investigate the role of γ-aminobutyric acid (GABA in PVN in regulating the AAR.Experiments were carried out in anesthetized rats. Renal sympathetic nerve activity (RSNA and mean arterial pressure (MAP were continuously recorded. AAR was evaluated by the RSNA and MAP responses to electrical stimulation of the right epididymal WAT (eWAT afferent nerve. Electrical stimulation of eWAT afferent nerve increase RSNA. Bilateral microinjection of the GABAA receptor agonist isoguvacine or the GABAB receptor agonist baclofen attenuated the AAR. The effect of isoguvacine on the AAR was greater than that of baclofen. The GABAA receptor antagonist gabazine enhanced the AAR, while the GABAB receptor antagonist CGP-35348 had no significant effect on the AAR. Bilateral PVN microinjection of vigabatrin, a selective GABA-transaminase inhibitor, to increase endogenous GABA levels in the PVN abolished the AAR. The inhibitory effect of vigabatrin on the AAR was attenuated by the pretreatment with gabazine or CGP-35348. Pretreatment with combined gabazine and CGP-35348 abolished the effects of vigabatrin.Activation of GABAA or GABAB receptors in the PVN inhibits the AAR. Blockade of GABAA receptors in the PVN enhances the AAR. Endogenous GABA in the PVN plays an important role in regulating the AAR.

  19. Presynaptic control of nociceptor signalling: Differential influence of Mu Opioid and GABAergic Systems

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    Ruth C Riley

    2000-01-01

    Full Text Available The relative contribution of pre- and postsynaptic controls to the flow of nociceptive information at the level of the spinal cord has been one of Ron Melzack's longstanding interests and a key issue in the formulation of the gate control theory. The authors review their own studies, in which they monitored internalization of the neurokinin-1 receptor to examine specifically the action of two classically inhibitory systems - mu opioid and gamma-amino butyric acid (GABA - on noxious stimulus-evoked tachykinin signalling in the rat spinal cord. Evidence that opioids and GABAergic controls operate differently on the central consequences of any noxious stimulus-induced substance P release is provided. Whereas at least 80% of the tachykinin signalling remained intact after even the highest concentration of spinal morphine or D-Ala2, NMe-phe4, Glyol5-enkephalin administration, spinal administration of the GABAB receptor agonist baclofen had a dramatic inhibitory effect. These findings are discussed in light of the disappointing clinical utility of baclofen and neurokinin-1 receptor antagonists to combat pain.

  20. The occurrence of the Babinski sign in complete spinal cord injury.

    Science.gov (United States)

    Petersen, Jens A; Schubert, Martin; Dietz, Volker

    2010-01-01

    The purpose of the present study was to explore factors that influence the occurrence of the Babinski sign (BS) in complete spinal cord injury patients. At Balgrist University Hospital, Zurich, Switzerland, thirty-five subjects suffering from a complete traumatic spinal cord injury (ASIA A) were examined for the occurrence of the BS, tendon reflex excitability and spastic muscle tone (Modified Ashworth Scale). Five subjects were acute/subacute (1-6 months after spinal cord injury (SCI)), 30 were chronic (SCI > 1 year). In one subject, the measures were examined before and after injection of intrathecal Baclofen. Subjects with a negative BS were investigated electrophysiologically for possible peripheral nerve damage. In 17 subjects (49%), the BS was present, while it was absent in 18 subjects (51%). The occurrence of the BS did not depend on the level of lesion. Most patients with a positive BS also presented a high spastic muscle tone, while those with a negative BS showed low level or absent spastic muscle tone. In 11 SCI subjects, absence of the BS was associated with peripheral nerve damage. In one patient, the BS along with spastic signs disappeared after intrathecal injection of Baclofen. In complete SCI subjects, the occurrence of the BS is connected with spastic muscle tone. The absence of the BS is frequently due to associated peripheral nerve damage.

  1. Heterogenous GABA(B) receptor-mediated pathways are involved in the local GABAergic system of the rat trigeminal ganglion: possible involvement of KCTD proteins.

    Science.gov (United States)

    Hayasaki, H; Sohma, Y; Kanbara, K; Otsuki, Y

    2012-08-30

    It is well known that Gamma-aminobutyric acid (GABA) plays an important role in signal transduction in the central nervous system. However, the function of GABA in the peripheral nervous system, including sensory ganglions, is still unclear. In this study we have characterized the expression, cellular distribution, and function of GABA(B) receptor subunits, and the recently discovered GABA(B) auxiliary subunits, K(+) channel tetramerization domain-containing (KCTD) proteins, in rat trigeminal ganglion (TG) neuronal cells, which are devoid of synapses. We found heterogeneous expression of both GABA(B1) and GABA(B2) subunits, and a near-plasma membrane localization of KCTD12. In addition, we found that GABA(B2) subunits correlated with KCTD16. Whole-cell current-clamp recordings showed that responses to the GABA(B) receptor agonist, baclofen, were variable and both increases and decreases in excitability were observed. This correlated with observed differences in voltage-dependent K(+) current responses to baclofen in voltage-clamped TG neuronal cells. The functional diversity of the GABA(B)ergic regulation on the excitability of the TG neuronal cell bodies could be due to the heterogenous expression of KCTD proteins, and subsequent regulation of plasma membrane K(+) channels. Taken together with our previous demonstration of a local GABA(A) receptor-mediated system in rat TG, we provide an updated GABAergic model in the rat TG that incorporates both GABA(A)- and GABA(B)-receptor systems.

  2. Vinpocetine and piracetam exert antinociceptive effect in visceral pain model in mice.

    Science.gov (United States)

    Abdel Salam, Omar M E

    2006-01-01

    The effect of vinpocetine or piracetam on thermal and visceral pain was studied in mice. In the hot plate test, vinpocetine (0.9 and 1.8 mg/kg), but not piracetam, produced a reduction in nociceptive response. Vinpocetine (0.45-1.8 mg/kg, ip) or piracetam (75-300 mg/kg, ip) caused dose-dependent inhibition of the abdominal constrictions evoked by ip injection of acetic acid. The effect of vinpocetine or piracetam was markedly potentiated by co-administration of propranolol, guanethidine, atropine, naloxone, yohimbine or prazosin. The marked potentiation of antinociception occurred upon a co-administration of vinpocetine and baclofen (5 or 10 mg/kg). In contrast, piracetam antagonized antinociception caused by the low (5 mg/kg), but not the high (10 mg/kg) dose of baclofen. The antinociception caused by vinpocetine was reduced by sulpiride; while that of piracetam was enhanced by haloperidol or sulpiride. Either vinpocetine or piracetam enhanced antinociception caused by imipramine. The antinociceptive effects of vinpocetine or piracetam were blocked by prior administration of theophylline. Low doses of either vinpocetine or piracetam reduced immobility time in the Porsolt's forced-swimming test. This study indicates that vinpocetine and piracetam possess visceral antinociceptive properties. This effect depends on activation of adenosine receptors. Piracetam in addition inhibits GABA-mediated antinociception.

  3. Clinical safety of magnetic resonance imaging in patients with implanted SynchroMed EL infusion pumps

    Energy Technology Data Exchange (ETDEWEB)

    Diehn, Felix E.; Wood, Christopher P.; Watson, Robert E.; Hunt, Christopher H. [Mayo Clinic, Department of Radiology, Rochester, MN (United States); Mauck, William D. [Mayo Clinic, Department of Anesthesiology, Rochester, MN (United States); Burke, Michelle M. [Mayo Clinic, Department of Psychiatry and Psychology, Rochester, MN (United States)

    2011-02-15

    Patients with implanted SynchroMed spinal infusion pumps (Medtronic, Inc., Minneapolis, MN) routinely undergo magnetic resonance imaging at our institution. In August 2008, Medtronic issued an urgent medical device correction report regarding several pumps. Because of the rare potential ''for a delay in the return of proper drug infusion'' and ''for a delay in the logging of motor stall events,'' ''a patient's pump must be interrogated after MRI exposure in order to confirm proper pump functionality.'' This is particularly important in patients receiving intrathecal baclofen, for whom a delay in return of proper pump infusion could lead to life-threatening baclofen withdrawal syndrome. The objective of this report is to present our experience and protocol of performing magnetic resonance imaging in patients with implanted SynchroMed EL pumps. We retrospectively reviewed records of 86 patients with implanted SynchroMed EL spinal infusion pumps who underwent 112 examinations on 1.5-T magnetic resonance imaging scanners from September 1, 1998 to July 7, 2004. No SynchroMed EL pumps were damaged by magnetic resonance imaging, and the programmable settings remained unchanged in all patients. Our data suggest that SynchroMed EL pump malfunction is indeed rare after routine clinical 1.5-T magnetic resonance imaging examinations. However, based on the Medtronic correction report, we perform pump interrogation before and after imaging. (orig.)

  4. GABAB and adenosine receptors mediate enhancement of the K+ current, IAHP, by reducing adenylyl cyclase activity in rat CA3 hippocampal neurons.

    Science.gov (United States)

    Gerber, U; Gähwiler, B H

    1994-11-01

    1. Gamma-aminobuturic acid-B (GABAB) and adenosine A1 receptors, which are expressed in hippocampal pyramidal cells, are linked to pertussis toxin-sensitive G-proteins known to be coupled negatively to the enzyme adenylyl cyclase. This study investigates the electrophysiological consequences of adenylyl cyclase inhibition in response to stimulation of these receptors. 2. Single-electrode voltage-clamp recordings were obtained from CA3 pyramidal cells in rat hippocampal slice cultures in presence of tetrodotoxin. The calcium-dependent potassium current (IAHP), which is very sensitive to intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP), was used as an electrophysiological indicator of adenylyl cyclase activity. 3. Application of baclofen (10 microM), a selective agonist at GABAB receptors, or adenosine (50 microM) each resulted in a transient decrease followed by a significant enhancement in the amplitude of evoked IAHP. The initial reduction in amplitude of IAHP probably reflects inadequacies in voltage clamp of electronically distant dendritic sites, due to the shunting caused by concomitant activation of potassium conductance by baclofen/adenosine. Comparable increases in membrane conductance in response to the GABAA agonist, muscimol, caused a similar reduction in IAHP. The enhancement of IAHP is consistent with an inhibition of constitutively active adenylyl cyclase. 4. The receptor mediating the responses to adenosine was identified as belonging to the A1 subtype on the basis of its sensitivity to the selective antagonist 8-cyclopentyl-1,3-dipropylxanthine.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. GabaB receptors activation in the NTS blocks the glycemic responses induced by carotid body receptor stimulation.

    Science.gov (United States)

    Lemus, Mónica; Montero, Sergio; Cadenas, José Luis; Lara, José Jesús; Tejeda-Chávez, Héctor Rafael; Alvarez-Buylla, Ramón; de Alvarez-Buylla, Elena Roces

    2008-08-18

    The carotid body receptors participate in glucose regulation sensing glucose levels in blood entering the cephalic circulation. The carotid body receptors information, is initially processed within the nucleus tractus solitarius (NTS) and elicits changes in circulating glucose and brain glucose uptake. Previous work has shown that gamma-aminobutyric acid (GABA) in NTS modulates respiratory reflexes, but the role of GABA within NTS in glucose regulation remains unknown. Here we show that GABA(B) receptor agonist (baclofen) or antagonists (phaclofen and CGP55845A) locally injected into NTS modified arterial glucose levels and brain glucose retention. Control injections outside NTS did not elicit these responses. In contrast, GABA(A) agonist and antagonist (muscimol or bicuculline) produced no significant changes in blood glucose levels. When these GABAergic drugs were applied before carotid body receptors stimulation, again, only GABA(B) agonist or antagonist significantly affected glycemic responses; baclofen microinjection significantly reduced the hyperglycemic response and brain glucose retention observed after carotid body receptors stimulation, while phaclofen produced the opposite effect, increasing significantly hyperglycemia and brain glucose retention. These results indicate that activation of GABA(B), but not GABA(A), receptors in the NTS modulates the glycemic responses after anoxic stimulation of the carotid body receptors, and suggest the presence of a tonic inhibitory mechanism in the NTS to avoid hyperglycemia.

  6. Stiff Person syndrome and other anti-GAD-associated neurologic disorders.

    Science.gov (United States)

    Dayalu, Praveen; Teener, James W

    2012-11-01

    Antibodies directed against glutamic acid decarboxylase (GAD) are present in many patients with stiff person syndrome and increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia. The classic clinical features of stiff person syndrome include muscular stiffness with superimposed painful muscular spasms. Gait is often impaired. Other CNS disorders associated with GAD antibodies include progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and even epilepsy. Glutamic acid decarboxylase is the rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter. Presumably, antibodies directed against GAD impair GABA production, but the precise pathogenic mechanism of GAD-antibody-related neurologic disorders is uncertain. Many patients respond to treatment with immunomodulating therapy. Symptomatic treatment with agents that enhance GABA activity, such as benzodiazepines and baclofen, is also helpful for many patients.

  7. Prevention of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    V A Parfenov

    2011-01-01

    Full Text Available The paper gives the data available in the literature on the treatment of spasticity in poststroke patients. Therapeutic exercises that should be started just on the first days of stroke are noted to play a leading role in the treatment of poststroke spasticity. The local administration of botulinum toxin preparations (botox, dysport, xeomin may be effective for managing local spasticity that deteriorates motor functions. Baclofen (baklosan, tizanidine (sirdalud, and tolperisone hydrochloride (mydocalm may be used as oral medications. The paper also presents the results of a placebo-controlled trial that has indicated that mydocalm given in a dose of 300 to 900 mg/day may be effective in treating poststroke spasticity.

  8. Identification and management of alcohol withdrawal syndrome.

    Science.gov (United States)

    Mirijello, Antonio; D'Angelo, Cristina; Ferrulli, Anna; Vassallo, Gabriele; Antonelli, Mariangela; Caputo, Fabio; Leggio, Lorenzo; Gasbarrini, Antonio; Addolorato, Giovanni

    2015-03-01

    Symptoms of alcohol withdrawal syndrome (AWS) may develop within 6-24 h after the abrupt discontinuation or decrease of alcohol consumption. Symptoms can vary from autonomic hyperactivity and agitation to delirium tremens. The gold-standard treatment for AWS is with benzodiazepines (BZDs). Among the BZDs, different agents (i.e., long-acting or short-acting) and different regimens (front-loading, fixed-dose or symptom-triggered) may be chosen on the basis of patient characteristics. Severe withdrawal could require ICU admission and the use of barbiturates or propofol. Other drugs, such as α2-agonists (clonidine and dexmetedomidine) and β-blockers can be used as adjunctive treatments to control neuroautonomic hyperactivity. Furthermore, neuroleptic agents can help control hallucinations. Finally, other medications for the treatment for AWS have been investigated with promising results. These include carbamazepine, valproate, sodium oxybate, baclofen, gabapentin and topiramate. The usefulness of these agents are discussed.

  9. Neurogenic cough.

    Science.gov (United States)

    Altman, Kenneth W; Noordzij, J Pieter; Rosen, Clark A; Cohen, Seth; Sulica, Lucian

    2015-07-01

    We review contemporary concepts of the pathophysiology of neurogenic cough, and its evaluation and treatment based on scientific publications addressing neurogenic cough. Neurogenic cough is thought to be the result of sensory neuropathy, most commonly idiopathic. Because it is principally a sensory phenomenon, clinical evaluation is challenging, the diagnosis most often being made by exclusion. Identification of motor paresis, either by laryngoscopy or laryngeal electromyography, may suggest the presence of sensory neuropathy. The utility of amitriptyline and gabapentin has been demonstrated in randomized clinical trials, and retrospective series and case reports have suggested efficacy of pregabalin, baclofen, and botulinum toxin. Sensory neuropathy appears to be an important cause of chronic refractory cough, and appears amenable to treatment with a variety of pharmacologic agents.

  10. [Misuse of alcohol and new drug treatments].

    Science.gov (United States)

    Paille, François

    2011-12-01

    Three drugs are currently marketed in France in the prevention of relapse in alcohol-dependent patients. Their efficacy though real remains limited and it is useful to develop other molecules. Some products are at present under evaluation, and are already or could be used in the near future in the treatment of alcohol dependence: baclofene, oxybate de sodium (GHB), nalmefene, topiramate, ondansetron and aripiprazole. The available studies on these molecules are still limited and the results sometimes clinically modest. Nevertheless, some of them open interesting future prospects. If there is no big revolution to wait in the short term in the treatment of alcohol dependence, we can consider some interesting orientations: better effectiveness on alcohol consumption, but also change of paradigm concerning the objectives and the methods of this treatment: reduction of consumption versus abstinence, treatment on request, choice of the molecule guided by objective criteria (psychosocial, biological, genetic...).

  11. Role of osteopathic manipulative treatment in the management of stiff person syndrome.

    Science.gov (United States)

    Rajaii, Roxanne M; Cox, Gregory J; Schneider, Robert P

    2015-06-01

    Stiff person syndrome (SPS) is a rare and disabling central nervous system disorder first described in 1956 and characterized by fluctuating rigidity and stiffness, gait impairment, and painful spasms of the axial and limb musculature. Although an underlying mechanism of impaired synaptic γ-aminobutyric acid-ergic inhibition has been proposed, the exact mechanism remains unclear. The glutamic acid decarboxylase antibody, a marker for SPS, is a strong indication of disease and has been reported in approximately 70% of patients. The current treatment of choice is benzodiazepines and baclofen, both of which reduce motor unit potential firing and, therefore, decrease stiffness and spasms. However, patients continue to have substantial disability with pharmacologic therapy alone. This case report demonstrates the potential of osteopathic manipulative treatment as an adjunct to medication in the management of SPS. By decreasing somatic dysfunction and reducing the frequency of exacerbations, osteopathic manipulative treatment may alleviate the symptoms and overall morbidity associated with this disease.

  12. Childhood-onset (Juvenile Huntington′s disease: A rare case report

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    Kailash Chandra Patra

    2015-01-01

    Full Text Available Huntington′s disease (HD is a rare dominantly inherited neurodegenerative disorder characterized clinically by a combination of abnormal involuntary (choreic movements, neuropsychiatric manifestations, and dementia. It is caused by an unstable CAG repeat expansion in the gene IT15 which encodes a Huntingtin protein. We present a case of a 9 year old boy who had developmental regression starting from the age of 8 years of age along with resistant seizures and signs of cerebellar involvement with absence of chorea and is on anticonvulsants, baclofen, and tetrabenzine. As is expected in a case of childhood-onset HD, our patient is rapidly deteriorating and is currently in the terminal phase of his illness along with resistant convulsions.

  13. G protein-coupled inwardly rectifying potassium channels in dorsal root ganglion neurons

    Institute of Scientific and Technical Information of China (English)

    Xiao-fei GAO; Hai-lin ZHANG; Zhen-dong YOU; Chang-lin LU; Cheng HE

    2007-01-01

    Aim: G protein-coupled inwardly rectifying potassium channels (GIRK) are important for neuronal signaling and membrane excitability. In the present study, we intend to find whether GIRK channels express functionally in adult rat dorsal root ganglion (DRG) neurons. Methods: We used RT-PCR to detect mRNA for4 subunits of GIRK in the adult DRG. The whole-cell patch clamp recording was used to confirm GIRK channels functionally expressed. Results: The mRNA for the 4 subunits of GIRK were detected in the adult DRG. GTPγS enhanced inwardly rectifying potassium (K+) currents of the DRG neurons, while Ba2+inhibited such currents. Furthermore, the GIRK channels were shown to be coupled to the GABAB receptor, a member of the G protein-coupled receptor family, as baclofen increased the inwardly rectifying K+ currents. Conclusion: GIRK channels are expressed and functionally coupled with GABAB receptors in adult rat DRG neurons.

  14. The Child with Cerebral Palsy and Anaesthesia

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    A Rudra

    2008-01-01

    Full Text Available Cerebral palsy (CP is the result of an injury to the developing brain during the antenatal, perinatal or postnatal period. Clinical manifestation relate to the areas affected. Patients with CP often present for elective surgical proce-dures to correct various deformities. Anaesthetic concerns of anaesthesia are intraoperative hypothermia , and slow emergence. Suxamethonium does not cause hyperkalaemia in these patients, and a rapid sequence induction may be indicated. Temperature should be monitored and an effort made to keep the patient warm. Cerebral abnormalities may lead to slow awakening; the patient should remain intubated until fully awake and airway reflexes have returned. Pulmonary infection can complicate the postoperative course. Postoperative pain management and the prevention of muscle spasms are important and drugs as baclofen and botulinum toxin are discussed. Epidural analgesia is particu-larly valuable when major orthopaedic procedures are performed.

  15. Low doses of alcohol potentiate GABA sub B inhibition of spontaneous activity of hippocampal CA1 neurons in vivo

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    Criado, J.R.; Thies, R. (Univ. of Oklahoma, Oklahoma City (United States))

    1991-03-11

    Low doses of alcohol facilitate firing of hippocampal neurons. Such doses also enhance the inhibitory actions of GABA. Alcohol is known to potentiate inhibition via GABA{sub A} receptors. However, the effects of alcohol on GABA{sub B} receptor function are not understood. Spontaneous activity of single units was recorded from CA1 neurons of male rats anesthetized with 1.0% halothane. Electrical recordings and local application of drugs were done with multi-barrel pipettes. CA1 pyramidal neurons fired spontaneous bursts of action potentials. Acute alcohol decreased the interval between bursts, a mild excitatory action. Alcohol also more than doubled the period of complete inhibition produced by local application of both GABA and baclofen. These data suggest that GABA{sub B}-mediated inhibition is also potentiated by low doses of alcohol.

  16. Neurochemical correlates of. gamma. -aminobutyrate (GABA) inhibition in cat visual cortex

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    Balcar, V.J.; Dreher, B. (Univ. of Sydney (Australia))

    1990-01-01

    High affinity binding of ({sup 3}H){gamma}-aminobutyric acid (GABA) to neuronal membranes from different parts of cat visual cortex was tested for sensitivity to GABA{sub A} agonists isoguvacine and THIP, GABA{sub A} antagonist SR95531 and GABA{sub B} agonist baclofen. Some of the GABA{sub A}-binding sites were found to have a very low affinity for THIP, suggesting the presence and, possibly, uneven distribution of non-synaptic GABA{sub A} receptors in cat visual cortex. There were no differences in K{sub m} and V{sub max} values of high affinity uptake of GABA and in the potency of K{sup +}-stimulated release of GABA, between primary and association cortices. Consequently, the present results indicate that despite the anatomical and physiological differences between the primary and association feline visual cortices the neurochemical characteristics of GABAergic inhibition are very similar in the two regions.

  17. GABAB受体与腺苷酸环化酶偶联环节的脱敏研究%STUDIES ON DESENSITIZATION OF GABAB RECEPTOR COUPLED ADENYLATE CYCLASE

    Institute of Scientific and Technical Information of China (English)

    俞在芳; 程冠军; 胡本荣

    1997-01-01

    将突触体膜与佛波酯(PMA),GABAB受体激动剂巴氯芬(Baclofen,BAL)预孵育一定时间后,BAL对腺苷酸环化酶(AC)基础活性及forskolin刺激的AC活性的抑制率显著降低(脱敏);而forskolin预孵育时,BAL对基础及forskolin刺激的AC活性的抑制率不变,表明GABAB受体与AC偶联环节的脱敏机制涉及蛋白激酶C(PKC)激活,而与蛋白激酶A无关,脱敏时GABAB受体的Kd值增加.本实验提示,可能由于PKC激活导致GABAB受体结构或构象改变,使受体-G蛋白脱偶联而出现脱敏现象.

  18. Update on neuropathic pain treatment for trigeminal neuralgia. The pharmacological and surgical options.

    Science.gov (United States)

    Al-Quliti, Khalid W

    2015-04-01

    Trigeminal neuralgia is a syndrome of unilateral, paroxysmal, stabbing facial pain, originating from the trigeminal nerve. Careful history of typical symptoms is crucial for diagnosis. Most cases are caused by vascular compression of the trigeminal root adjacent to the pons leading to focal demyelination and ephaptic axonal transmission. Brain imaging is required to exclude secondary causes. Many medical and surgical treatments are available. Most patients respond well to pharmacotherapy; carbamazepine and oxcarbazepine are first line therapy, while lamotrigine and baclofen are considered second line treatments. Other drugs such as topiramate, levetiracetam, gabapentin, pregabalin, and botulinum toxin-A are alternative treatments. Surgical options are available if medications are no longer effective or tolerated. Microvascular decompression, gamma knife radiosurgery, and percutaneous rhizotomies are most promising surgical alternatives. This paper reviews the medical and surgical therapeutic options for the treatment of trigeminal neuralgia, based on available evidence and guidelines.

  19. Antihyperglycemic, antistress and nootropic activity of roots of Rubia cordifolia Linn.

    Science.gov (United States)

    Patil, Rupali A; Jagdale, Swati C; Kasture, Sanjay B

    2006-12-01

    Effect of alcoholic extract of roots of Rubia cordifolia was studied on elevated blood glucose level in alloxan treated animals. The extract reduced the blood sugar level raised by alloxan. Effect of alcoholic extract was also investigated on cold restraint induced stress and on scopolamine-induced memory impairment. Alcoholic extract enhanced brain gamma-amino-n-butyric acid (GABA) levels and decreased brain dopamine and plasma corticosterone levels. Acidity and ulcers caused due to cold restraint stress were inhibited by alcoholic extract. Animals treated with alcoholic extract spent more time in open arm in elevated plus maze model. It also antagonized scopolamine induced learning and memory impairment. Baclofen induced catatonia was potentiated by alcoholic extract.

  20. Role of dopamine and GABA in the control of motor activity elicited from the rat nucleus accumbens.

    Science.gov (United States)

    Wong, L S; Eshel, G; Dreher, J; Ong, J; Jackson, D M

    1991-04-01

    The application of 1.2 and 12.0 micrograms/side of the GABAA receptor agonist 3-aminopropane sulphonic acid bilaterally into the nucleus accumbens (Acb) of rats nonsignificantly depressed locomotor activity as assessed in automated Animex activity cages, while the highest dose (60 micrograms/side) significantly stimulated activity. The GABAA receptor antagonists picrotoxinin (0.0625 and 0.125 micrograms/saide) and bicuculline (0.895 micrograms/side) produced forward locomotion around the cage accompanied by a number of other behaviours. The GABAB agonist baclofen (0.023 and 0.092 micrograms/side) induced a short-lasting (18 min) locomotor depression. None of the GABAB antagonists tested (2-hydroxysaclofen 2.6 micrograms/side, two novel beta-(benzo[b]furan) analogues of baclofen 9G or 9H each 6.8 micrograms/side, 4-aminobutylphosphonic acid 1.32 micrograms/side and phaclofen 0.535 and 2 micrograms/side) significantly affected locomotor activity. In rats pretreated with reserpine and alpha-methyl-p-tyrosine, picrotoxinin (0.0625 and 0.125 micrograms/side) did not significantly alter locomotor activity. Furthermore, when picrotoxinin (0.0625 micrograms/side) was combined with either the selective dopamine (DA) D1 agonist SKF38393 or the selective D2 agonist quinpirole, no significant alteration in locomotor function occurred. When SKF38393 and quinpirole were coadministered, significant stimulation occurred which was further enhanced by the addition of picrotoxinin. It is concluded that GABAA receptors, together with D1 and D2 receptors, play a major role in modulating the control of motor function by the Acb of rats.

  1. gamma-Hydroxybutyrate (GHB) induces GABA(B) receptor independent intracellular Ca2+ transients in astrocytes, but has no effect on GHB or GABA(B) receptors of medium spiny neurons in the nucleus accumbens.

    Science.gov (United States)

    Molnár, T; Antal, K; Nyitrai, G; Emri, Z

    2009-08-18

    We report on cellular actions of the illicit recreational drug gamma-hydroxybutyrate (GHB) in the brain reward area nucleus accumbens. First, we compared the effects of GHB and the GABA(B) receptor agonist baclofen. Neither of them affected the membrane currents of medium spiny neurons in rat nucleus accumbens slices. GABAergic and glutamatergic synaptic potentials of medium spiny neurons, however, were reduced by baclofen but not GHB. These results indicate the lack of GHB as well as postsynaptic GABA(B) receptors, and the presence of GHB insensitive presynaptic GABA(B) receptors in medium spiny neurons. In astrocytes GHB induced intracellular Ca(2+) transients, preserved in slices from GABA(B) receptor type 1 subunit knockout mice. The effects of tetrodotoxin, zero added Ca(2+) with/without intracellular Ca(2+) store depletor cyclopiazonic acid or vacuolar H-ATPase inhibitor bafilomycin A1 indicate that GHB-evoked Ca(2+) transients depend on external Ca(2+) and intracellular Ca(2+) stores, but not on vesicular transmitter release. GHB-induced astrocytic Ca(2+) transients were not affected by the GHB receptor-specific antagonist NCS-382, suggesting the presence of a novel NCS-382-insensitive target for GHB in astrocytes. The activation of astrocytes by GHB implies their involvement in physiological actions of GHB. Our findings disclose a novel profile of GHB action in the nucleus accumbens. Here, unlike in other brain areas, GHB does not act on GABA(B) receptors, but activates an NCS-382 insensitive GHB-specific target in a subpopulation of astrocytes. The lack of either post- or presynaptic effects on medium spiny neurons in the nucleus accumbens distinguishes GHB from many drugs and natural rewards with addictive properties and might explain why GHB has only a weak reinforcing capacity.

  2. Unusually severe case of dermatosis neglecta.

    Science.gov (United States)

    Turrentine, Jake E; Blalock, Travis W; Davis, Loretta S

    2012-01-01

    An 18-year-old black woman with cerebral palsy was admitted for evaluation of an intrathecal baclofen pump site infection. The dermatology service was consulted for treatment suggestions of a presumed diagnosis of chronic tinea capitis. Three courses of oral griseofulvin during the past 2 years failed to resolve the patient's chronic scalp dermatosis. Scalp lesions first began about 2 years earlier after hospitalization for placement of an intrathecal baclofen pump. The patient was unable to care for her scalp due to her cerebral palsy, and her mother interpreted the scalp condition as infectious. No routine shampoo care, scalp care, or topical treatment was performed for more than 1 1/2 years. The mother felt that touching the patient's scalp might cause pain and noted that the majority of her time was spent concentrating on more critical medical issues. Physical examination revealed coalescing hyperkeratotic plaques extending dorsally from the anterior hairline to the occipital scalp with small flecks of keratinous debris throughout the remaining hair (Figure 1). The plate-like plaques were devoid of hair, except at a few fissures where a few tufts of hair emerged. No cervical lymph nodes were appreciated on palpation. Treatment was initiated with compresses consisting of large warm water-soaked towels 4 times daily. Three times a day, a nursing staff applied 5% salicylic acid in olive oil to the scalp under a shower cap for approximately 1 hour. Over the following 2 days, a significant reduction in keratinous debris was appreciated. Within 2 weeks, the bulk of the plaques had been removed (Figure 2). At 6-week follow-up, the underlying scalp showed areas of fibrosis and possible scarring with a few emerging tufts of hair. On the basis of history and response to treatment with salicylic acid and routine scalp care, the patient was diagnosed with an unusually severe case of dermatosis neglecta.

  3. Deep brain stimulation of the globus pallidus internus (GPI) for torsion dystonia--a report of two cases.

    Science.gov (United States)

    Vesper, J; Klostermann, F; Funk, Th; Stockhammer, F; Brock, M

    2002-01-01

    Generalized dystonia is known as a type of movement disorder in which pharmacotherapeutic options are very limited. Deep Brain Stimulation (DBS) is well established for Parkinson's disease (PD) and tremor dominant movement disorders. We report on two cases of generalized dystonia which were successfully treated by chronic high frequency stimulation in the Globus pallidus internus (GPI). Two 26 and 27 years old males suffered from severe torsion dystonia and multisegmental dystonia of the lower limbs. Case 1 is a familiar type of dystonia (DYT1 positive). The onset of symptoms in both cases was at age 7. The complaints were initially treated with orally administered benzodiazepines, anticholinergic drugs, later by baclofen and L-DOPA. However there was no response. Case 2 was a patient with a history of left side dominated dystonia since the age of 8. It was first diagnosed as a psychogenic movement disorder. Prior to surgery he was treated with L-DOPA, anticholinergics, Baclofen without any effect. There was only a limited effect on high doses of diazepam. The patient is DYT1 negative. The target point was on both sides the GPI. Intraoperative computerized tomography (CT) and ventriculography (VG) were used for target setting. Furthermore microrecordings were helpful to ensure the exact electrode position. Surgery was performed under analgosedation. Two weeks after surgery we first observed a relief of symptoms in both cases. A significant reduction in the Burke-Fahn-Marsden-Dystonia Movement Rating Scale was observed at the 6 month follow-up (case 1: 95%, case 2: 80%). In case 1 a slight dystonic movement of the left ankle was the only remaining symptom under stimulation. The medication was continuously reduced. At the 24 month follow-up the effect of stimulation remained unchanged. However high stimulation parameters are required to maintain an optimal effect (mean 3.5 V, 400 microseconds, 145 Hz).

  4. The GABA(B) receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats.

    Science.gov (United States)

    Li, Xia; Kaczanowska, Katarzyna; Finn, M G; Markou, Athina; Risbrough, Victoria B

    2015-10-01

    GABAB (γ-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABAB receptor positive allosteric modulator (PAM) BHF177 on conditioned and unconditioned physiological responses to threat in the light-enhanced startle (LES), stress-induced hyperthermia, and fear-potentiated startle (FPS) procedures in rats. The effects of BHF177 on LES were compared with those of the GABAB receptor agonists baclofen and CGP44532, and the positive control buspirone, a 5-HT1A receptor partial agonist with anxiolytic activity in humans. Baclofen (0.4, 0.9 and 1.25 mg/kg) and CGP44532 (0.065, 0.125 and 0.25 mg/kg) administration had significant sedative, but not anxiolytic, activity reflected in overall decrease in the startle response in the LES tests. BHF177 (10, 20 and 40 mg/kg) had no effect on LES, nor did it produce an overall sedative effect. Interesting, however, when rats were grouped by high and low LES responses, BHF177 had anxiolytic-like effects only on LES in high, but not low, LES responding rats. BHF177 also blocked stress-induced hyperthermia, but had no effect on conditioned fear responses in the FPS test. Buspirone (1 and 3 mg/kg) had an anxiolytic-like profile in both LES and FPS tests. These results indicate that BHF177 may specifically attenuate unconditioned anxiety in individuals that exhibit a high anxiety state, and has fewer sedative effects than direct agonists. Thus, BHF177 or other GABAB receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared to GABAB receptor agonists.

  5. A critical role of lateral hypothalamus in context-induced relapse to alcohol seeking after punishment-imposed abstinence.

    Science.gov (United States)

    Marchant, Nathan J; Rabei, Rana; Kaganovsky, Konstantin; Caprioli, Daniele; Bossert, Jennifer M; Bonci, Antonello; Shaham, Yavin

    2014-05-28

    In human alcoholics, abstinence is often self-imposed, despite alcohol availability, because of the negative consequences of excessive use. During abstinence, relapse is often triggered by exposure to contexts associated with alcohol use. We recently developed a rat model that captures some features of this human condition: exposure to the alcohol self-administration environment (context A), after punishment-imposed suppression of alcohol self-administration in a different environment (context B), provoked renewal of alcohol seeking in alcohol-preferring P rats. The mechanisms underlying context-induced renewal of alcohol seeking after punishment-imposed abstinence are unknown. Here, we studied the role of the lateral hypothalamus (LH) and its forebrain projections in this effect. We first determined the effect of context-induced renewal of alcohol seeking on Fos (a neuronal activity marker) expression in LH. We next determined the effect of LH reversible inactivation by GABAA + GABAB receptor agonists (muscimol + baclofen) on this effect. Finally, we determined neuronal activation in brain areas projecting to LH during context-induced renewal tests by measuring double labeling of the retrograde tracer cholera toxin subunit B (CTb; injected in LH) with Fos. Context-induced renewal of alcohol seeking after punishment-imposed abstinence was associated with increased Fos expression in LH. Additionally, renewal was blocked by muscimol + baclofen injections into LH. Finally, double-labeling analysis of CTb + Fos showed that context-induced renewal of alcohol seeking after punishment-imposed abstinence was associated with selective activation of accumbens shell neurons projecting to LH. The results demonstrate an important role of LH in renewal of alcohol seeking after punishment-imposed abstinence and suggest a role of accumbens shell projections to LH in this form of relapse.

  6. Resolution of chronic migraine headaches with intrathecal ziconotide: a case report

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    Narain S

    2015-09-01

    Full Text Available Sachin Narain,1 Lama Al-Khoury,2 Eric Chang3–6 1Department of Anesthesiology and Perioperative Care, 2Department of Neurology, 3Department of Physical Medicine and Rehabilitation, 4Department of Neurosurgery, 5Department of Orthopedics, 6Reeve-Irvine Research Center for Spinal Cord Injury, University of California Irvine, Irvine, CA, USA Background: Migraine headaches are a common and functionally debilitating disorder affecting approximately 17% of women and 5.6% of men. Compared to episodic migraine patients, chronic migraineurs are more likely to be occupationally disabled, miss family activities, have comorbid anxiety and/or chronic pain disorders, and utilize significantly more health care dollars. Ziconotide is a calcium channel blocker used for the treatment of chronic severe pain without issues of tolerance or dependency found with opioid therapy. Case: A 59-year-old female had an intrathecal baclofen pump placed for spasticity secondary to multiple sclerosis. Her symptoms also included lower extremity neuropathic pain and severe migraine headaches with 22 migraine headache days per month. Prior treatments included nonsteroidal anti-inflammatory drugs, triptans, anticonvulsants, antihypertensives, and Botox injections which reduced her symptoms to four migraine days per month at best. While her spasticity had markedly improved with intrathecal baclofen, ziconotide was added to help her neuropathic pain complaints. Following initiation of low-dose ziconotide (1 µg/day, the patient noted both lower extremity pain improvement and complete resolution of migraine headaches resulting in zero migraine days per month. She has now been migraine free for 8 months. Conclusion: Upon review of the available literature, there are no published cases of migraine improvement with intrathecal ziconotide. This represents the first case describing resolution of migraine symptoms with low-dose ziconotide. Keywords: ziconotide, migraine, symptoms, chronic

  7. GABAA receptors modulate cannabinoid-evoked hypothermia.

    Science.gov (United States)

    Rawls, S M; Tallarida, R J; Kon, D A; Geller, E B; Adler, Martin W

    2004-05-01

    Cannabinoids evoke hypothermia by stimulating central CB(1) receptors. GABA induces hypothermia via GABA(A) or GABA(B) receptor activation. CB(1) receptor activation increases GABA release in the hypothalamus, a central locus for thermoregulation, suggesting that cannabinoid and GABA systems may be functionally linked in body temperature regulation. We investigated whether GABA receptors modulate the hypothermic actions of [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one] (WIN 55212-2), a selective cannabinoid agonist, in male Sprague-Dawley rats. WIN 55212-2 (2.5 mg/kg im) produced a rapid hypothermia that peaked 45-90 min postinjection. The hypothermia was attenuated by bicuculline (2 mg/kg ip), a GABA(A) antagonist. However, SCH 50911 (1-10 mg/kg ip), a GABA(B) blocker, did not antagonize the hypothermia. Neither bicuculline (2 mg/kg) nor SCH 50911 (10 mg/kg) by itself altered body temperature. We also investigated a possible role for CB(1) receptors in GABA-generated hypothermia. Muscimol (2.5 mg/kg ip), a GABA(A) agonist, or baclofen (5 mg/kg ip), a GABA(B) agonist, evoked a significant hypothermia. Blockade of CB(1) receptors with SR141716A (2.5 mg/kg im) did not antagonize muscimol- or baclofen-induced hypothermia, indicating that GABA-evoked hypothermia does not contain a CB(1)-sensitive component. Our results implicate GABA(A) receptors in the hypothermic actions of cannabinoids and provide further evidence of a functional link between cannabinoid and GABA systems.

  8. Roles of forebrain GABA receptors in controlling vasopressin secretion and related phenomena under basal and hyperosmotic circumstances in conscious rats.

    Science.gov (United States)

    Yamaguchi, Ken'ichi; Yamada, Takaho

    2008-09-05

    Although the anteroventral third ventricular region (AV3V), a forebrain area essential for homeostatic responses, includes receptors for gamma-aminobutyric acid (GABA), the roles of these receptors in controlling vasopressin (AVP) secretion and related phenomena have not been clarified as yet. This study aimed to pursue this problem in conscious rats implanted with indwelling catheters. Cerebral injection sites were determined histologically. Applications of bicuculline, a GABA(A) receptor antagonist, to the AV3V induced prompt and marked augmentations in plasma AVP, osmolality, glucose, arterial pressure and heart rate, without affecting plasma electrolytes. Such phenomena did not occur when phaclofen, a GABA(B) receptor antagonist, was applied to the AV3V. All of the effects of AV3V-administered bicuculline were abolished by preadministration of the GABA(A) receptor agonist muscimol. Preadministration of either MK-801 or NBQX, ionotropic glutamatergic receptor antagonists, was also potent to abolish the AVP response to AV3V bicuculline. When hypertonic saline was infused intravenously, plasma AVP increased progressively, in parallel with rises in plasma osmolality, sodium and arterial pressure. AV3V application of muscimol or baclofen, a GABA(B) receptor agonist, was found to abolish the response of plasma AVP, without inhibiting that of the osmolality or sodium. The response of arterial pressure was also blocked by muscimol treatment, but not by baclofen treatment. Based on these results, we concluded that, under basal conditions, GABA receptors in the AV3V or vicinity may tonically operate to attenuate AVP secretion and cardiovascular functions through mechanisms associated with glutamatergic activity, and that plasma hyperosmolality may cause facilitation of AVP release by decreasing forebrain GABAergic activity.

  9. Neural Mechanisms and Delayed Gastric Emptying of Liquid Induced Through Acute Myocardial Infarction in Rats

    Energy Technology Data Exchange (ETDEWEB)

    Nunez, Wilson Ranu Ramirez; Ozaki, Michiko Regina; Vinagre, Adriana Mendes; Collares, Edgard Ferro; Almeida, Eros Antonio de, E-mail: erosaa@cardiol.br [Universidade Estadual de Campinas, Campinas, SP (Brazil)

    2015-02-15

    In pathological situations, such as acute myocardial infarction, disorders of motility of the proximal gut can trigger symptoms like nausea and vomiting. Acute myocardial infarction delays gastric emptying (GE) of liquid in rats. Investigate the involvement of the vagus nerve, α 1-adrenoceptors, central nervous system GABA{sub B} receptors and also participation of paraventricular nucleus (PVN) of the hypothalamus in GE and gastric compliance (GC) in infarcted rats. Wistar rats, N = 8-15 in each group, were divided as INF group and sham (SH) group and subdivided. The infarction was performed through ligation of the left anterior descending coronary artery. GC was estimated with pressure-volume curves. Vagotomy was performed by sectioning the dorsal and ventral branches. To verify the action of GABA{sub B} receptors, baclofen was injected via icv (intracerebroventricular). Intravenous prazosin was used to produce chemical sympathectomy. The lesion in the PVN of the hypothalamus was performed using a 1mA/10s electrical current and GE was determined by measuring the percentage of gastric retention (% GR) of a saline meal. No significant differences were observed regarding GC between groups; vagotomy significantly reduced % GR in INF group; icv treatment with baclofen significantly reduced %GR. GABA{sub B} receptors were not conclusively involved in delaying GE; intravenous treatment with prazosin significantly reduced GR% in INF group. PVN lesion abolished the effect of myocardial infarction on GE. Gastric emptying of liquids induced through acute myocardial infarction in rats showed the involvement of the vagus nerve, alpha1- adrenergic receptors and PVN.

  10. Neural Mechanisms and Delayed Gastric Emptying of Liquid Induced Through Acute Myocardial Infarction in Rats

    Directory of Open Access Journals (Sweden)

    Wilson Ranu Ramirez Nunez

    2015-02-01

    Full Text Available Background: In pathological situations, such as acute myocardial infarction, disorders of motility of the proximal gut can trigger symptoms like nausea and vomiting. Acute myocardial infarction delays gastric emptying (GE of liquid in rats. Objective: Investigate the involvement of the vagus nerve, α 1-adrenoceptors, central nervous system GABAB receptors and also participation of paraventricular nucleus (PVN of the hypothalamus in GE and gastric compliance (GC in infarcted rats. Methods: Wistar rats, N = 8-15 in each group, were divided as INF group and sham (SH group and subdivided. The infarction was performed through ligation of the left anterior descending coronary artery. GC was estimated with pressure-volume curves. Vagotomy was performed by sectioning the dorsal and ventral branches. To verify the action of GABAB receptors, baclofen was injected via icv (intracerebroventricular. Intravenous prazosin was used to produce chemical sympathectomy. The lesion in the PVN of the hypothalamus was performed using a 1mA/10s electrical current and GE was determined by measuring the percentage of gastric retention (% GR of a saline meal. Results: No significant differences were observed regarding GC between groups; vagotomy significantly reduced % GR in INF group; icv treatment with baclofen significantly reduced %GR. GABAB receptors were not conclusively involved in delaying GE; intravenous treatment with prazosin significantly reduced GR% in INF group. PVN lesion abolished the effect of myocardial infarction on GE. Conclusion: Gastric emptying of liquids induced through acute myocardial infarction in rats showed the involvement of the vagus nerve, alpha1- adrenergic receptors and PVN.

  11. Evidences for the involvement of monoaminergic and GABAergic systems in antidepressant-like activity of garlic extract in mice

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    Dhingra Dinesh

    2008-01-01

    Full Text Available Objectives: The present study was undertaken to investigate the effect of the ethanolic extract of Allium sativum L. (Family: Lilliaceae, commonly known as garlic, on depression in mice. Materials and Methods: Ethanolic extract of garlic (25, 50 and 100 mg/kg was administered orally for 14 successive days to young Swiss albino mice of either sex and antidepressant-like activity was evaluated employing tail suspension test (TST and forced swim test (FST. The efficacy of the extract was compared with standard antidepressant drugs like fluoxetine and imipramine. The mechanism of action of the extract was investigated by co-administration of prazosin (α1-adrenoceptor antagonist, sulpiride (selective D2-receptor antagonist, baclofen (GABA B agonist and p-CPA (serotonin antagonist separately with the extract and by studying the effect of the extract on brain MAO-A and MAO-B levels. Results: Garlic extract (25, 50 and 100 mg/kg significantly decreased immobility time in a dose-dependent manner in both TST and FST, indicating significant antidepressant-like activity. The efficacy of the extract was found to be comparable to fluoxetine (20 mg/kg p.o. and imipramine (15 mg/kg p.o. in both TST and FST. The extract did not show any significant effect on the locomotor activity of the mice. Prazosin, sulpiride, baclofen and p-CPA significantly attenuated the extract-induced antidepressant-like effect in TST. Garlic extract (100 mg/kg administered orally for 14 successive days significantly decreased brain MAO-A and MAO-B levels, as compared to the control group. Conclusion: Garlic extract showed significant antidepressant-like activity probably by inhibiting MAO-A and MAO-B levels and through interaction with adrenergic, dopaminergic, serotonergic and GABAergic systems.

  12. 孕烯醇酮和孕烯醇酮硫酸盐对小鼠不同脑区3H-GABA与GABAB受体结合的影响%Effects of Pregnenolone and Pregnenolone Sulfate on 3H-GABA Bound with GABAB Receptor in Different Areas of Mice Brain

    Institute of Scientific and Technical Information of China (English)

    周雪瑞

    2001-01-01

    By using radioactive ligand-receptor binding assay, this paperreported the effects of pregnenolong (Pe) and pregnenolone sulfate (Pes) on 3H-GABA bound with GABAB receptor in different areas of mice brain. The result showed that Pe decreased the binding of 3H-GABA with GABAB receptor, and it could be blocked and turned over by baclofen. Pes markedly decreased the binding of 3H-GABA with GABAB receptor in cerebral cortex and hippocampus and increased the binding in hypothalamus of mice brain. Baclofen could blocked the inhibition effect, enhance the effects of increase. These results suggested that major effects of Pe and Pes on 3H-GABA bound with GABAB receptor in different areas of mice brain were inhibition effects.%采用放射配体受体结合分析法,研究了孕烯醇酮(Pe)和孕烯醇酮硫酸盐(Pes)对小鼠不同脑区3H-GABA与GABAB受体结合的影响.结果显示,Pe对小鼠下丘脑、大脑皮层、海马、小脑GABAB受体的结合均有抑制效应,且能被GABAB受体激动剂巴氯芬(Bac)所阻断并翻转.Pes对大脑皮层、海马、小脑GABAB受体的结合有抑制作用,而对下丘脑则有促进作用.Bac能阻断Pes的抑制作用(海马除外),加强Pes的促进作用.实验结果提示,Pe,Pes对各脑区GABAB受体的结合具有一定的影响作用,且多为抑制效应.

  13. 针康法对脑卒中后痉挛状态的影响%Effect of Cluster Needling of Scalp Acupuncture Combined with Rehabilitation on Spasticity after Stroke

    Institute of Scientific and Technical Information of China (English)

    关莹; 张立; 邢艳丽; 唐强

    2011-01-01

    目的探讨针康法对腩卒中后痉挛状态的作用.方法将39例脑卒中后肢体痉挛的患者随机分为观察组和对照组.观察组采用针康法抗痉挛针法配合康复治疗方法,对照组采用巴氯芬配合康复治疗.用改良Ashworth法和Barthel指数评定肌张力、日常生活活动能力(ADL)和临床疗效.结果与对照组比较,观察组肌张力分级、ADL评分、临床疗效无显著性差异(P>0.05).结论针康法在改善卒中后痉挛方面与药物治疗效果相同,且无严重副作用.%Objective To explore the effect of cluster needling of scalp acupuncture combined with rehabilitation (Tang's Approach) on the spasticity after stroke. Methods 39 stroke patients with spasm were divided into observation group and control group.The observation group received anti-spasm acupuncture combined with rehabilitation therapy, while the control group received baclofen combined with rehabilitation therapy. Spasm and activities of daily living(ADL) and therapeutical effect were assessed with the Modified Ashworth Scale and Barthel Index. Results There was no significant difference between the two groups (P>0. 05).Conclusion Tang's Approach has the same effect as baclofen to improve the spasm after stroke without serious side-effect.

  14. Effect of activation of γ-aminobutyric acid B receptors on glutamate release in spinal dorsal horn neurons in rats with diabetic neuropathic pain%激活γ-氨基丁酸B受体对糖尿病神经痛大鼠脊髓背角神经元谷氨酸递质释放的影响

    Institute of Scientific and Technical Information of China (English)

    王秀丽; 吴川; 郭跃先; 王秋筠; 刘飞飞; 曹倩倩; 张兆龙

    2012-01-01

    目的 探讨激活γ-氨基丁酸B(γ-aminobutyric acid B,GABAB)受体对糖尿病神经痛大鼠脊髓背角谷氨酸能神经元递质释放中的影响.方法 30只(4周龄,150 g~170 g)雄性Sprague-Dawley( SD)大鼠,采用随机数字表法随机分为2组(每组15只):正常对照组(N组)、糖尿病神经痛组(D组).D组通过腹腔注射链脲佐菌素(streptozotocin,STZ)50 mg/kg制备糖尿病神经痛模型,N组腹腔给予等量生理盐水,两组分别于腹腔注射后第3~4周测定空腹血糖、机械缩足阈值(paw withdrawal mechanical threshold,PWMT);然后处死大鼠取腰1~5脊髓,制备脊髓薄片,采用全细胞膜片钳技术,记录脊髓Ⅱ板层单突触神经元谷氨酸能诱发兴奋性突触后电流(evoked excitatory postsynaptic currents,eEPSCs).细胞封接后稳定5 min开始记录,灌流液中加入终浓度为1、10、20、50μmol/L的Baclofen(GABAB受体特异性激动剂),于给药前对照、给予上述浓度药后各时点及洗脱后5 min,记录上述各时点eEPSCs的波幅变化,比较Baclofen对两组大鼠eEPSCs波幅的抑制率,并观察CGP55845 (GABAB 受体特异性阻断剂,1 μmol/L)对Baclofen(50 μmol/L)eEPSCs作用的影响.结果 与N组比较,D组大鼠血糖显著增高,PWT明显降低(P<0.05).电生理共记录30个神经元(每组15个),1 μmol/L~50 μmol/L的Baclofen均以剂量依赖方式降低两组大鼠eEPSCs波幅(P<0.05),N、D两组在1、10、20、50 μmol/L Baclofen时点波幅抑制率均明显下降(P<0.05),两组上述时点比较,D组显著低于N组(P<0.05),分别为:(47±7)vs(21±7),(55±6)vs(50±6),(92±6)vs(72±9),(95±8)vs(88±8),1μmol/LCGP55845可完全去除50 μmol/L Baclofen对两组神经元(每组12个)eEPSCs的作用.结论 激活GABAB受体可明显抑制脊髓背角神经元谷氨酸递质释放,但对糖尿病神经痛大鼠其抑制作用减弱.%Objective To explore the effect of activation of γ-aminobutyric acid B (GABAB) receptors on glutamate

  15. Dihydrocodeine / Agonists for Alcohol Dependents

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    Albrecht eUlmer

    2012-03-01

    Full Text Available Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients.Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC to 102 heavily alcohol addict-ed patients, later, also Buprenorphine, Clomethiazole (>6 weeks, Baclofen and in one case Amphetamine, each on individual indication. This paper focuses on the data with DH, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC-treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-step scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details.Conclusions: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around ¼ of the patients already. Many further

  16. Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.

    Science.gov (United States)

    Bassi, Gabriel S; do C Malvar, David; Cunha, Thiago M; Cunha, Fernando Q; Kanashiro, Alexandre

    2016-08-01

    Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.

  17. TMS-EEG signatures of GABAergic neurotransmission in the human cortex.

    Science.gov (United States)

    Premoli, Isabella; Castellanos, Nazareth; Rivolta, Davide; Belardinelli, Paolo; Bajo, Ricardo; Zipser, Carl; Espenhahn, Svenja; Heidegger, Tonio; Müller-Dahlhaus, Florian; Ziemann, Ulf

    2014-04-16

    Combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) constitutes a powerful tool to directly assess human cortical excitability and connectivity. TMS of the primary motor cortex elicits a sequence of TMS-evoked EEG potentials (TEPs). It is thought that inhibitory neurotransmission through GABA-A receptors (GABAAR) modulates early TEPs (TMS), whereas GABA-B receptors (GABABR) play a role for later TEPs (at ∼100 ms after TMS). However, the physiological underpinnings of TEPs have not been clearly elucidated yet. Here, we studied the role of GABAA/B-ergic neurotransmission for TEPs in healthy subjects using a pharmaco-TMS-EEG approach. In Experiment 1, we tested the effects of a single oral dose of alprazolam (a classical benzodiazepine acting as allosteric-positive modulator at α1, α2, α3, and α5 subunit-containing GABAARs) and zolpidem (a positive modulator mainly at the α1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a GABABR agonist) and diazepam (a classical benzodiazepine) versus placebo on TEPs. Alprazolam and diazepam increased the amplitude of the negative potential at 45 ms after stimulation (N45) and decreased the negative component at 100 ms (N100), whereas zolpidem increased the N45 only. In contrast, baclofen specifically increased the N100 amplitude. These results provide strong evidence that the N45 represents activity of α1-subunit-containing GABAARs, whereas the N100 represents activity of GABABRs. Findings open a novel window of opportunity to study alteration of GABAA-/GABAB-related inhibition in disorders, such as epilepsy or schizophrenia.

  18. Sleep-deprivation regulates α-2 adrenergic responses of rat hypocretin/orexin neurons.

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    Aaron Uschakov

    Full Text Available We recently demonstrated, in rat brain slices, that the usual excitation by noradrenaline (NA of hypocretin/orexin (hcrt/orx neurons was changed to an inhibition following sleep deprivation (SD. Here we describe that in control condition (CC, i.e. following 2 hours of natural sleep in the morning, the α(2-adrenergic receptor (α(2-AR agonist, clonidine, had no effect on hcrt/orx neurons, whereas following 2 hours of SD (SDC, it hyperpolarized the neurons by activating G-protein-gated inwardly rectifying potassium (GIRK channels. Since concentrations of clonidine up to a thousand times (100 µM higher than those effective in SDC (100 nM, were completely ineffective in CC, a change in the availability of G-proteins is unlikely to explain the difference between the two conditions. To test whether the absence of effect of clonidine in CC could be due to a down-regulation of GIRK channels, we applied baclofen, a GABA(B agonist known to also activate GIRK channels, and found that it hyperpolarized hcrt/orx neurons in that condition. Moreover, baclofen occluded the response to clonidine in SDC, indicating that absence of effect of clonidine in CC could not be attributed to down-regulation of GIRK channels. We finally tested whether α(2-ARs were still available at the membrane in CC and found that clonidine could reduce calcium currents, indicating that α(2-ARs associated with calcium channels remain available in that condition. Taken together, these results suggest that a pool of α(2-ARs associated with GIRK channels is normally down-regulated (or desensitized in hcrt/orx neurons to only become available for their inhibition following sleep deprivation.

  19. γ-aminobutyric acid B receptor (GABABR)ameliorated liver fibrosis by inhibiting hepatic cell migration%γ-氨基丁酸B受体抑制大鼠肝细胞迁移并改善肝纤维化

    Institute of Scientific and Technical Information of China (English)

    樊文梅; 石炳毅; 冯凯; 马锡慧; 魏红山; 黄海燕; 何秀云

    2012-01-01

    Objective To investigate the role of r-aminobutyric acid B receptor in the development of liver fibrosis.Methods Thirty-two Sprague-Dawley (SD) rats were divided into four groups including a control group,a model group,a baclofen group,and a CGP35348 group.Liver fibrosis was then induced by carbon tetrachloride (CCl4).Baclofen and CGP35348 treatment were carried out after the formation of liver fibrosis,followed by complete extraction of the eyeball to obtain blood sample to test liver function.Liver tissue specimens were cut and stored for histological staining,histochemistry,real-time polymerase chain-reaction (RT-PCR),and western blot analysis.Results Histological staining indicated that the degree of liver fibrosis was more severe in the CGP35348 group than in the baclofen group (P<0.001).The levels of alanine transaminase (ALT),aspartate aminotransferase (AST),gamma-glutamyl transferase (GGT),total bilirubin (TBil),and direct bilirubin (DBil) were significantly lower in the baclofen group than in the CGP35348 group (P<0.01).The levels of ALT,AST,GGT,TBil,and DBil were significantly higher in the CGP35348 group than in the model group (P<0.05).Immunofluorescence results show that the hepatic cell migration was inhibited in the baclofen group.Western blot results showed that the expression levels of α-SMA protein were significantly lowered in the baclofen group when compared to that of the CGP35348 group and model group (P<0.01).Conclusion GABAB receptor might play a role in the liver protection by inhibition of migration of hepatic cells in liver fibrosis.Further studies into the mechanism behind this function are further needed and may be a potential source of future anti-fibrotic treatment.%目的 探讨发现γ-氨基丁酸B(GABAB)受体对肝纤维化的调控作用.方法 32只SD 大鼠分为4组,每组8只,分别为对照组、模型组、baclofen处理组和CGP35348处理组.用四氯化碳(CCl4)溶液诱导肝纤维化,baclofen和CGP35348处

  20. γ-氨基丁酸及B受体在胃癌SGC-7901细胞中表达及对细胞迁移能力的影响%Influence of the expressions of GABA and GABABR1 in gastric cancer SGC-7901 cells on cell migration ability

    Institute of Scientific and Technical Information of China (English)

    史良会; 张才全

    2011-01-01

    目的 观察GABA,GAD65,GABABR1在胃癌SGC-7901细胞中的表达及对细胞迁移能力的影响.方法 RT-PCR、IF及Western印迹检测胃癌细胞SGC-7901中GABA、GAD65及GABABRI mRNA及蛋白表达;不同浓度GABA,Baclofen及CGP35348作用于胃癌细胞SGC-7901细胞24h,transwell细胞迁移小室检测细胞迁移能力的变化.结果 GAD65,GABABR1 mRNA及蛋白表达于SGC-7901细胞中;GABA,GABABR1及GAD65蛋白定位于SGC-7901细胞胞膜、胞质;与空白组比较,随着GABA浓度的增加,细胞迁移能力增强;5μmol/L及50 μmol/L baelofen作用后,亦可促进细胞迁移;而随着CGP35348浓度的增加,细胞穿膜数量减少(P<0.01).5μmol/L baclofen对细胞的迁移促进作用可被100 μmol/L的CGP35348逆转.结论 GABA及其B受体在SGC-7901细胞中的高表达可促进细胞迁移.%Objective To investigate the expressions of GABA, GAD65 and GABABR1 in SGC-7901 cells and the effects of cell migration. Methods RT-PCR, IF and Western blot were used to detect the expressions of GABA, GAD65 and GABABR1 in gastric cancer cells SGC-7901. SGC-7901 cells were cultured in transwell chamer for 24 h with different concentrations of GABA, baclofen and CGP35348. The number of cells which migrated through micropores and stayed on the outer bottom side of insert systems were observed and counted. Results The mRNA and protein expressions of GABA, GAD65 and GABRP in SGC-7901 cells were significantly higher than those in normal gastric mucosa (P<0. 01). GABA, GAD65 and GABRP protein levels were predominantly localized on the cell membrane and cell cytoplasm of SGC-7901. Compared with that of blank group, the migration capability of SGC-7901 was obviously increased by the higher concentration of GABA and 5, 50 μmol/L Baclofen, but significantly inhibited by 5, 50 (μmol/L Bicuculline (P <0. 01). The effect of 5 μmol/L Baclofen was blocked by pretreatment with 100 μmol/L CGP35348. Conclusions Higher expressions of GABA and GABRP in

  1. Tibolone Rapidly Attenuates the GABAB Response in Hypothalamic Neurones

    Science.gov (United States)

    Qiu, Jian; Bosch, Martha A.; Rønnekleiv, Oline K.; Kloosterboer, Helenius J.; Kelly, Martin J.

    2008-01-01

    Tibolone is primarily used for the treatment of climacteric symptoms. Tibolone is rapidly converted into three major metabolites: 3α- and 3β-hydroxy-tibolone (3α- and 3βOH-tibolone), which have oestrogenic effects, and the Δ4-isomer (Δ4-tibolone), which has progestogenic and androgenic effects. Since tibolone is effective in treating climacteric symptoms, the effects on the brain may be explained by the oestrogenic activity of tibolone. Previously using whole-cell patch clamp recording, we found that 17β-oestradiol (E2) rapidly altered GABA neurotransmission in hypothalamic neurones through a membrane oestrogen receptor (mER). E2 reduced the potency of the GABAB receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K+ channels in hypothalamic neurones. Therefore, we hypothesized that tibolone may have some rapid effects through the mER and sought to elucidate the signalling pathway of tibolone’s action using selective inhibitors and whole cell recording in ovariectomized female guinea pigs and mice. A sub-population of neurones was identified post hoc as proopiomelanocortin (POMC) neurones by immunocytochemical staining. Similar to E2, we have found that tibolone and its active metabolite 3βOH-tibolone rapidly reduced the potency of the GABAB receptor agonist baclofen to activate GIRK channels in POMC neurones. The effects were blocked by the ER antagonist ICI 182,780. Other metabolites of tibolone (3αOH-tibolone and Δ4-tibolone) had no effect. Furthermore, tibolone (and 3βOH-tibolone) was fully efficacious in ERαKO and ERβKO mice to attenuate GABAB responses. The effects of tibolone were blocked by phospholipase C inhibitor U73122. However, in contrast to E2, the effects of tibolone were not blocked by protein kinase C inhibitors or protein kinase A inhibitors. It appears that tibolone (and 3βOH-tibolone) activates phospholipase C leading to PIP2 metabolism and direct alteration of GIRK channel function. Therefore, tibolone

  2. Clinical potential, safety, and tolerability of arbaclofen in the treatment of autism spectrum disorder

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    Frye RE

    2014-05-01

    Full Text Available Richard E FryeArkansas Children's Hospital Research Institute, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USAAbstract: Autism spectrum disorder (ASD is a behaviorally defined disorder which has increased in prevalence over the last two decades. Despite decades of research, no effective treatment is currently available. Animal models, as well as other lines of evidence, point to abnormalities in the balance of cortical excitation to inhibition in individuals with ASD, with this imbalance resulting in an overall increase in cortical excitation. To reduce cortical excitatory glutamate pathways, arbaclofen, a selective agonist of the gamma aminobutyric acid receptor type B, has been developed. This article reviews the evidence for this treatment for ASD using a systematic review methodology. Overall, a systematic search of the literature revealed 148 relevant references with the majority of these being review papers or news items that mentioned the potential promise of arbaclofen. Five original studies were identified, four of which used STX209, a form of arbaclofen developed by Seaside Therapeutics, Inc., and one which used R-baclofen. In an animal model, treatment of Fragile X, a genetic disease with ASD features, demonstrated a reversal of behavioral, neurological, and neuropathological features associated with the disease. One double-blind, placebo-controlled study treated children and adults with Fragile X. Results from this study were promising, with signs of improvement in social function, especially in the most severely socially impaired. Two studies, one open-label and one double-blind, placebo-controlled, were conducted in children, adolescents, and young adults with ASD. These studies suggested some improvements in socialization, although the effects were limited and may have been driven by individuals with ASD that were higher-functioning. These studies and others that have used arbaclofen for

  3. Advances in the management of multiple sclerosis spasticity: multiple sclerosis spasticity guidelines.

    Science.gov (United States)

    Gold, Ralf; Oreja-Guevara, Celia

    2013-12-01

    Symptomatic therapy of multiple sclerosis (MS) is an important part of a comprehensive treatment plan that aims to improve patients' quality of life. In the current era of medical progress, several factors have led to the development of guidelines for MS management. There is continued need for an evidence-based approach supported by high-quality data from controlled clinical trials. Most healthcare systems require this approach and include it in the reimbursement process. Guidelines are usually committed by national or continental neurological societies. The Spanish Society of Neurology demyelinating diseases working group has developed a consensus document on spasticity in patients with MS. MS experts from the group used the metaplan method to sum up the most important recommendations about spasticity for inclusion in the guidance. Recommendations were classified according to the Scottish Intercollegiate Guidelines Network system and approved by all members of the group. In Germany, the guideline panel of the German Neurological Society endorsed the national competence network for multiple sclerosis (Krankheitsbezogenes Kompetenznetz Multiple Sklerose) to update the existing recommendations. The most recent fifth edition of the guidelines (dated April 2012) now also includes recommendations for treatment of key symptoms such as spasticity. More than 30 MS neurologists contributed to the new edition reflecting the need for broad expertise. After a first round in which key topics were defined, a web-based decision process was undertaken to further develop individual topics such as symptomatic therapy. The draft manuscript was reviewed once again by the group prior to submission to the official review process. The aims of spasticity treatment are to improve mobility and dexterity, achieve physiological movement patterns, reduce pain, facilitate nursing measures and avoid complications such as contractures. Representative antispasticity medications include baclofen

  4. Tratamento da doença de Meige com droga agonista de receptores GABA

    Directory of Open Access Journals (Sweden)

    Luiz Augusto Franco de Andrade

    1985-09-01

    Full Text Available A doença de Meige é distúrbio de movimento que consiste no aparecimento espontâneo de blefarospasmo associado a movimentos distônicos de musculatura orofacial. Associadamene podem ser encontrados torcicolo espasmódico, disfonia espástica e distonia de extremidades. Várias hipóteses foram formuladas para explicar esse distúrbio, tendo em vista a resposta a drogas com ação conhecida nos sistemas de neurotransmissores do cérebro. Algumas evidências apontam para um estado de preponderância dopaminérgica e, nesse sentido, justifica-se a estimulação da atividade GABA, sabendo-se que esse neurotrans-missor age sobre uma das alças de controle da produção de dopamina na substância negra. Por essa razão investigamos a ação de um agonista GABA, o baclofen, sobre a doença de Meige. Foram incluídos no protocolo 5 pacientes, 4 mulheres e um homem, com idade variando entre 50 e 63 anos e duração da doença variando entre 4 meses e 18 anos. Todos apresentavam blefaros-pasmo-distonia orofacial e, além disso três apresentavam disfonia espástica e um distonia de extremidades. A droga era iniciada em dose de 20mg/dia, aumentada em lOmg a cada três dias até ser obtida resposta ou surgirem efeitos colaterais. Um dos pacientes apresentou melhora marcada do blefaros-pasmo-distonia orofacial e outro melhora moderada dos mesmos sintomas, em avaliação 30 dias após estabilização da dose. Não houve melhora da disfonia espástica e ocorreu melhora moderada da distonia de extremidades. Não podemos afirmar que a melhora observada ao fim de um mês se mantenha, ou mesmo que melhora mais significativa fosse observada em avaliação feita mais tardiamente. Concluimos que o baclofen pode ser útil, pelo menos por algum tempo, na doença de Meige.

  5. 拮抗针法结合改良强制性运动疗法对脑梗死后上肢痉挛状态的影响%Effect of Modified Constraint Induced Movement Combined with Antagonistic Acupuncture Therapy on Upper Limb Spastic Hemiplegia after Cerebral Infarction

    Institute of Scientific and Technical Information of China (English)

    杨加顺; 孙茹; 王绚; 王虹; 张居婵; 高潇

    2016-01-01

    Objective:To study the effect of modified constraint induced movement combined with antagonistic acupuncture therapy on upper limb spastic hemiplegia after cerebral infarction .Methods:100 patients with cer-ebral infarction were divided randomly into two groups ,a control group (50 cases) with baclofen therapy and a treatment group ( 50 cases ) with modified constraint induced movement combined with antagonistic acupunc-ture therapy .The modified Ashworth Score and Fugl Meyer Assessment were used to evaluate the efficacy be-fore and after treatment .Results:In the treatment group the scores of Ashworth Score and FMA of upper limbs increased more significantly than those in the control group (P﹤0.01,P﹤0.05).Conclusion:Modified con-straint induced movement combined with antagonistic acupuncture therapy is better than baclofen therapy .%目的::研究拮抗针法结合改良强制性运动疗法对脑梗死患者上肢痉挛状态的影响。方法:将符合纳入标准100例脑梗死上肢痉挛状态患者随机分为拮抗针法结合改良强制性运动疗组(治疗组)和巴氯芬组(对照组),各50例。采用改良Ashworth分级评定法和Fugl Meyer 运动功能(FMA)评分法评价临床疗效。结果:治疗组治疗后Ashworth及FMA评分优于对照组(P﹤0.01,P﹤0.05)。结论:拮抗针法结合改良强制性运动疗法能显著改善脑梗死后的上肢痉挛状态,综合临床疗效优于巴氯芬。

  6. 苍白球GABAB受体对氟哌啶醇制备帕金森病模型大鼠姿势行为的影响%EFFECT OF ACTIVATION OF GABAB RECEPTOR IN GLOBUS PALLIDUS ON POSTURE BEHAVIOR IN RATS

    Institute of Scientific and Technical Information of China (English)

    王宏韬; 崔巧玲; 陈蕾

    2008-01-01

    目的 观察苍白球γ-氨基丁酸B型(GABAB)受体激活对氟哌啶醇诱发的帕金森病大鼠姿势行为的影响.方法 单侧苍白球埋置套管,恢复3 d后,腹腔注射氟哌啶醇(1 mg/kg)诱发帕金森病僵硬大鼠模型.于4组模型大鼠苍白球分别微量注射生理盐水、GABAB受体激动剂baclofen (1 mmol/L)、GABAB受体阻断剂CGP55845(0.1 mmol/L)、CGP55845和baclofen的混合物,注射体积为0.5 μL,观察其偏转行为的变化.结果单侧苍白球微量注射baclofen,大鼠立刻出现明显的同侧偏转行为,与盐水对照组比较,差异有统计学意义(u=8.5,P<0.001);而单侧苍白球微量注射CGP55845可产生明显的对侧偏转行为(u=22.0,P<0.001);同时注入baclofen和CGP55845混合物,动物呈现微弱的对侧偏转行为,与单纯注射baclofen相比,差异有统计学意义(u=3.5,P<0.001).结论 阻断苍白球GABAB受体可减轻氟哌啶醇所致的神经元兴奋性降低,从而解除基底神经节对丘脑及大脑皮质运动区的抑制效应,导致运动功能增强,提示其可能起抗帕金森病的作用.

  7. Thoracic 9 Spinal Transection-Induced Model of Muscle Spasticity in the Rat: A Systematic Electrophysiological and Histopathological Characterization.

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    Jose A Corleto

    Full Text Available The development of spinal hyper-reflexia as part of the spasticity syndrome represents one of the major complications associated with chronic spinal traumatic injury (SCI. The primary mechanism leading to progressive appearance of muscle spasticity is multimodal and may include loss of descending inhibitory tone, alteration of segmental interneuron-mediated inhibition and/or increased reflex activity to sensory input. Here, we characterized a chronic thoracic (Th 9 complete transection model of muscle spasticity in Sprague-Dawley (SD rats. Isoflurane-anesthetized rats received a Th9 laminectomy and the spinal cord was transected using a scalpel blade. After the transection the presence of muscle spasticity quantified as stretch and cutaneous hyper-reflexia was identified and quantified as time-dependent changes in: i ankle-rotation-evoked peripheral muscle resistance (PMR and corresponding electromyography (EMG activity, ii Hoffmann reflex, and iii EMG responses in gastrocnemius muscle after paw tactile stimulation for up to 8 months after injury. To validate the clinical relevance of this model, the treatment potency after systemic treatment with the clinically established anti-spastic agents baclofen (GABAB receptor agonist, tizanidine (α2-adrenergic agonist and NGX424 (AMPA receptor antagonist was also tested. During the first 3 months post spinal transection, a progressive increase in ankle rotation-evoked muscle resistance, Hoffmann reflex amplitude and increased EMG responses to peripherally applied tactile stimuli were consistently measured. These changes, indicative of the spasticity syndrome, then remained relatively stable for up to 8 months post injury. Systemic treatment with baclofen, tizanidine and NGX424 led to a significant but transient suppression of spinal hyper-reflexia. These data demonstrate that a chronic Th9 spinal transection model in adult SD rat represents a reliable experimental platform to be used in studying the

  8. Obsessive-compulsive disorder, impulse control disorders and drug addiction: common features and potential treatments.

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    Fontenelle, Leonardo F; Oostermeijer, Sanne; Harrison, Ben J; Pantelis, Christos; Yücel, Murat

    2011-05-07

    ), glutamate (e.g. topiramate), serotonin (e.g. ondansetron) or γ-aminobutyric acid (e.g. baclofen and topiramate) systems, may prove to show some benefit in certain forms of OCD. Based on the available evidence, we suggest that the treatment of patients with these disorders must account for alterations in the underlying motivations and neurobiology of the condition. We provide an initial guide to the specific treatments that future clinical trials might consider in patients with OCD. For example, it might be wise to test naltrexone in patients with co-morbid SUD and ICD, topiramate in patients with co-morbid ICD and eating disorders, and baclofen in patients with co-morbid Tourette's syndrome. These trials could also include scales aimed at assessing underlying impulsivity (e.g. Barratt Impulsiveness Scale) to check whether this construct might predict response to drugs acting on the reward system.

  9. The effect of BLA GABAB receptors in anxiolytic-like effect and aversive memory deficit induced by ACPA

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    Katayoon Kangarlu Haghighi

    2016-07-01

    Full Text Available Background: As a psychoactive plant, Cannabis sativa (Marijuana is widely used throughout the world. Several investigations have indicated that administration of Marijuana affects various cognitive and non-cognitive behaviors. These include anxiety-like behaviors and learning and memory deficit. It has been shown that three main cannabinoid receptors [i.e. CB1, CB2 and CB3 are involved in cannabinoids’ functions. CB1 receptors are abundantly expressed in the central nervous system regions such as hippocampus, amygdala, cerebellum and the cortex. Therefore, the neuropsychological functions of endocannabinoids are thought to be more linked to CB1 receptors. Among other brain regions, CB1 is highly expressed in the amygdala which is an integral component of the limbic circuitry. The amygdala plays a major role in the control of emotional behavior, including conditioned fear and anxiety. In present study we examined the possible roles of basolateral amygdala (BLA GABAB receptors in arachydonilcyclopropylamide (ACPA-induced anxiolytic-like effect and aversive memory deficit in adult male mice. Methods: This experimental study was conducted from September 2013 to December 2014 in Institute for Studies in Theoretical Physics and Mathematics, School of Cognitive Sciences, Tehran and Male albino NMRI mice (Pasture Institute, Iran, weighting 27-30 g, were used. Bilateral guide-cannulae were implanted to allow intra BLA microinjection of the drugs. We used Elevated Plus Maze (EPM to examine memory and anxiety behavior (test-retest protocol. ACPA administrate intra-peritoneal and GABAB agonist and antagonist administrated intra-amygdala. Results: Data showed that pre-test treatment with ACPA induced anxiolytic-like and aversive memory deficit The results revealed that pre-test intra-BLA infusion of baclofen (GABAB receptor agonist impaired the aversive memory while phaclofen (GABAB receptor antagonist improved it. Interestingly, pretreatment with a sub

  10. Incidence estimate and guideline-oriented treatment for post-stroke spasticity: an analysis based on German statutory health insurance data

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    Egen-Lappe V

    2013-03-01

    Full Text Available Veronika Egen-Lappe, Ingrid Köster, Ingrid SchubertPMV Research Group, Department of Child and Adolescence Psychiatry and Psychotherapy, University of Cologne, Cologne, GermanyBackground: Spasticity after stroke has been internationally recognized as an important health problem causing impairment of mobility, deformity, and pain. The aim of this study was to assess the frequency of first-ever and recurrent stroke and of subsequent spastic and flaccid paresis. Factors influencing the development of spasticity were analyzed. A further major aim was to provide a "real-life" assessment of the treatment of spasticity in Germany and to discuss this in view of the treatment recommended by German and international clinical guidelines.Methods: The database used in this study comprised a cohort of 242,090 insurants from a large statutory health insurance fund in the federal state of Hesse, Germany. A first hospital discharge diagnosis in 2009 with any of the International Classification of Diseases, Tenth Revision (ICD-10 codes I60–I64 was used to identify patients with acute stroke (hemorrhage and ischemic. These patients were followed up six months after stroke to monitor whether they developed spastic or flaccid paresis (hospital or ambulatory care diagnoses ICD-10 code G81–G83 [excluding G82.6/G83.4/G83.8]. For patients with spastic paresis after stroke the spasticity treatment was analyzed for a six-month period (physiotherapy, oral muscle relaxants, intrathecal baclofen, and botulinum toxin.Results: Standardized to the population of Germany, 3.7 per 1000 persons suffered a stroke in 2009 (raw 5.2/1000. Of all surviving patients, 10.2% developed spasticity within 6 months. Cox regression revealed no significant influence of patient age, gender, morbidity (diabetes, hypertensive diseases, ischemic heart diseases or type of stroke on development of spasticity. 97% of surviving patients with spasticity received physiotherapy (inpatient care 89

  11. Electrophysiological recordings and calcium measurements in striatal large aspiny interneurons in response to combined O2/glucose deprivation.

    Science.gov (United States)

    Pisani, A; Calabresi, P; Centonze, D; Marfia, G A; Bernardi, G

    1999-05-01

    potential was mimicked by oxotremorine, an M2-like muscarinic receptor agonist, and by baclofen, a GABAB receptor agonist. However, this membrane hyperpolarization was not coupled to an increase but rather to a decrease of the basal [Ca2+]i. Furthermore glibenclamide did not reduce the oxotremorine- and baclofen-induced membrane hyperpolarization. In conclusion, the present results suggest that in striatal LA cells, O2/glucose deprivation activates a membrane hyperpolarization that does not involve ligand-gated K+ conductances but is sensitive to barium, glibenclamide, and charybdotoxin. The increase in [Ca2+]i is partially due to influx through voltage-gated high-voltage-activated Ca2+ channels.

  12. Statistical Design of Experiments on Fabrication of Bilayer Tablet of Narrow Absorption Window Drug: Development and In vitro characterisation.

    Science.gov (United States)

    Jivani, R R; Patel, C N; Jivani, N P

    2012-07-01

    The current study involves the fabrication of oral bioadhesive bilayer matrices of narrow absorption window drug baclofen and the optimisation of their in vitro drug release and characterisation. Statistical design of experiments, a computer-aided optimisation technique, was used to identify critical factors, their interactions and ideal process conditions that accomplish the targeted response(s). A central composite design was employed to systematically optimise the drug delivery containing a polymer, filler and compression force. The values of ratio of different grades of hydroxypropyl methylcellulose, microcrystalline cellulose and compression force were varied to be fitted in design. Drug release at 1 h (Q1), 4 h (Q4), 8 h (Q8), 12 h (Q12), and hardness were taken as responses. Tablets were prepared by direct compression methods. The compressed tablets were evaluated for their hardness, weight variation, friability, content uniformity and diameter. Counter plots were drawn and optimum formulation was selected by desirability function. The formulations were checked for their ex vivo mucoadhesion. The experimental value of Q1, Q4, Q8, Q12 and hardness for check-point batch was found to be 31.64, 45.82, 73.27, 98.95% and 4.4 kg/cm(2), respectively. The release profile indicates Highuchi kinetics (Fickian transport) mechanism. The results of the statistical analysis of the data demonstrated significant interactions amongst the formulation variables, and the desirability function was demonstrated to be a powerful tool to predict the optimal formulation for the bilayer tablet.

  13. Combined Anterior and Posterior Lumbar Rhizotomy for Treatment of Mixed Dystonia and Spasticity in Children With Cerebral Palsy

    Science.gov (United States)

    Nada, Mohamed; Mahran, Mahmoud A.; Aboud, Ahmed; Mahran, Moustafa G.; Nasef, Marwa A.A.; Gaber, Mohamed; Sabry, Tamer; Ibrahim, Mohamed H.; Taha, Mohamed H.

    2016-01-01

    BACKGROUND: Children with cerebral palsy (CP) can present with severe secondary dystonia with or without associated spasticity of their extremities. OBJECTIVE: To assess the outcomes of combined anterior and posterior lumbar rhizotomy for the treatment of mixed hypertonia in the lower extremities of children with CP. METHODS: Fifty children with CP were subjected to combined anterior and posterior lumbar rhizotomies in a prospective study. Clinical outcome measurements were recorded preoperatively and were evaluated at 2, 6, and 12 months postoperatively. The operative techniques were performed by laminotomy from L1-S1, and intraoperative monitoring was used in all cases. All patients underwent intensive postoperative physiotherapy programs. RESULTS: Changes in muscle tone, joint range of motion, and dystonia were significant (P = .000) at postoperative assessment visits. CONCLUSION: This study demonstrated the potential of combined anterior and posterior lumbar rhizotomies to improve activities of daily living in children with CP and with mixed spasticity and dystonia. ABBREVIATIONS: BAD, Barry-Albright Dystonia Scale CAPR, combined anterior and posterior lumbar rhizotomy CP, cerebral palsy ITB, intrathecal baclofen MAS, modified Ashworth Scale ROM, range of motion SDR, selective dorsal rhizotomy PMID:27244465

  14. Dystonic storm due to Batten's disease treated with pallidotomy and deep brain stimulation.

    Science.gov (United States)

    Elkay, Muruvet; Silver, Kenneth; Penn, Richard D; Dalvi, Arif

    2009-05-15

    To report a novel treatment approach, pallidotomy and deep brain stimulation (DBS), in two sisters with dystonic storm due to Batten's disease. This study is based on long-term follow-up of two sisters, presenting with dystonic storm and their response to pallidotomy and DBS. These sisters, who had visual loss, seizures, and progressive psychomotor decline, experienced progressive disabling abnormal movements culminating in dystonic storm at the age of 15 and 17 years, respectively. In addition to intubation and sedation, multiple medications, including botulinum toxin injections and intrathecal baclofen infusion were tried in both patients without any benefit. The old sister underwent bilateral pallidotomy. Within 10 days postoperatively, there was marked improvement in dystonic storm. She was free of abnormal movements for 9 months. Then she started having opisthotonus lasting 20 seconds to an hour several times/day, but over 6 years abnormal movements are markedly improved, and not returned to pre-pallidotomy level. The young sister underwent both bilateral pallidotomy and DBS, 3 weeks apart. She was free of abnormal movements for 7 months and able to maintain reduction in the abnormal movements by adjusting DBS settings. Pallidotomy and DBS should be considered in dystonic storm due to Batten's disease.

  15. Differential effects of phosphonic analogues of GABA on GABA(B) autoreceptors in rat neocortical slices.

    Science.gov (United States)

    Ong, J; Marino, V; Parker, D A; Kerr, D I

    1998-04-01

    The effects of five phosphonic derivatives of GABA on the release of [3H]-GABA from rat neocortical slices, preloaded with [3H]-GABA, were investigated. Phaclofen and 4-aminobutylphosphonic acid (4-ABPA) increased the overflow of [3H] evoked by electrical stimulation (2 Hz) in a concentration-dependent manner, with similar potencies (phaclofen EC50=0.3 mmol/l, 4-ABPA EC50=0.4 mmol/l). At 3 mmol/l, phaclofen increased the release of [3H]-GABA by 82.6+/-8.6%, and 4-ABPA increased the release by 81.3+/-9.0%. 2-Amino-ethylphosphonic acid (2-AEPA) increased the overflow of [3H] by 46.8+/-10.9% at the highest concentration tested (3 mmol/l). In contrast, the lower phosphonic homologue 3-aminopropylphosphonic acid (3-APPA), and 2-amino-2-(p-chlorophenyl)-ethylphosphonic acid (2-CPEPA), a baclofen analogue, did not modify the stimulated overflow. These results suggest that phaclofen, 4-ABPA and 2-AEPA are antagonists at GABA(B) autoreceptors, the latter being the weakest antagonist, whilst neither 3-APPA nor 2-CPEPA are active at these receptors. Since phaclofen, 4-ABPA and 2-CPEPA are antagonists and 3-APPA a partial agonist/antagonist on GABA(B) heteroreceptors, the lack of effect of 3-APPA and 2-CPEPA on [3H]-GABA release in this study suggests that GABA(B) autoreceptors may be pharmacologically distinct from the heteroreceptors.

  16. Identification of Drugs in Parenteral Pharmaceutical Preparations from a Quality Assurance and a Diversion Program by Direct Analysis in Real-Time AccuTOFTM-Mass Spectrometry (DART-MS).

    Science.gov (United States)

    Poklis, Justin L; Mohs, Amanda J; Wolf, Carl E; Poklis, Alphonse; Peace, Michelle R

    2016-10-01

    In healthcare settings drug diversion and impairment of physicians are major concerns requiring a rapid and efficient method for surveillance and detection. A Direct Analysis in Real Time ion source coupled to a JEOL AccuTOF(TM) time-of-flight mass spectrometer (DART-MS) method was developed to screen parenteral pharmaceutical formulations for potential drug diversion. Parenteral pharmaceutical formulations are also known as injectable formulations and are used with intravenous, subcutaneous, intramuscular and intra-articular administration. A library was created using the mass spectra data collected by a DART-MS operated in switching mode at 20, 60 and 90 V settings. This library contained 17 commonly encountered drugs in parenteral pharmaceutical formulations that included the surgical analgesic: fentanyl, hydromorphone and morphine; anesthetic: baclofen, bupivacaine, ketamine, midazolam, ropivacaine and succinylcholine; and a mixture of other drug classes: caffeine, clonidine, dexamethasone, ephedrine, heparin, methadone, oxytocin and phenylephrine. Randomly selected 200 de-identified parenteral pharmaceutical formulations containing one or more drugs were submitted for analysis to the FIRM Toxicology Laboratory at Virginia Commonwealth University Health and were screened using the DART-MS. The drug contents of the de-identified formulations were previously confirmed by a published high performance liquid chromatography (HPLC) method. The drugs in the formulations were rapidly and successfully identified using the generated library. The DART-MS and HPLC results were in complete agreement for all 200 parenteral pharmaceutical formulations.

  17. Are the effects of gamma-hydroxybutyrate (GHB) treatment partly physiological in alcohol dependence?

    Science.gov (United States)

    Ameisen, Olivier

    2008-01-01

    It has been hypothesized that the therapeutic effects of Gamma-hydroxybutyrate (GHB) in alcohol dependence could be related to ethanol-mimicking action of the drug and that GHB could reduce alcohol craving, intake and withdrawal by acting as a "substitute" of the alcohol in the central nervous system. Nevertheless, alcohol being the strongest trigger of craving and intake, it is difficult to ascribe reduction of craving and intake to ethanol-mimicking activity of GHB. I have recently proposed that alcohol/substance dependence could result from a GHB-deficiency-related dysphoric syndrome in which alcohol/substances would be sought to "substitute" for insufficient GHB effect. GHB is the sole identified naturally occurring gamma-aminobutyric acid B (GABA (B)) receptor agonist. Here, I propose that exogenous GHB might in fact "substitute" for deficient endogeneous GHB and represent true substitutive treatment for GHB-deficiency. And that baclofen and GHB could both compensate for deficient effect of the physiological GABA (B) receptor agonist(s).

  18. Modulation of Visceral Nociception, Inflammation and Gastric Mucosal Injury by Cinnarizine

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    Omar M.E. Abdel-Salam

    2007-01-01

    Full Text Available The effect of cinnarizine, a drug used for the treatment of vertigo was assessed in animal models of visceral nociception, inflammation and gastric mucosal injury. Cinnarizine (1.25–20 mg/kg, s.c. caused dose-dependent inhibition of the abdominal constrictions evoked by i.p. injection of acetic acid by 38.7–99.4%. This effect of cinnarizine (2.5 mg/kg was unaffected by co-administration of the centrally acting dopamine D2 receptor antagonists, sulpiride, haloperidol or metoclopramide, the peripherally acting D2 receptor antagonist domperidone, but increased by the D2 receptor agonist bromocryptine and by the non-selective dopamine receptor antagonist chlorpromazine. The antinociception caused by cinnarizine was naloxone insenstive, but enhanced by propranolol, atropine and by yohimbine. The antinociceptive effect of cinnarizine was prevented by co-treatment with the adenosine receptor blocker theophylline or by the ATP-sensitive potassium channel (KATP blocker glibenclamide. Cinnarizine at 2.5 mg/kg reversed the baclofen-induced antinociception. Cinnarizine at 2.5 mg/kg reduced immobility time in the Porsolt’s forced-swimming test by 24%. Cinnarizine inhibited the paw oedema response to carrageenan and reduced gastric mucosal lesions caused by indomethacin in rats. It is suggested that cinnarizine exerts anti-infl ammatory, antinociceptive and gastric protective properties. The mechanism by which cinnarizine modulates pain transmission is likely to involve adenosine receptors and KATP channels.

  19. Paraneoplastic degeneration of the substantia nigra with dystonia and parkinsonism.

    Science.gov (United States)

    Golbe, L I; Miller, D C; Duvoisin, R C

    1989-01-01

    A 42-year-old woman suffered unexplained weight loss followed by action tremor and difficulty initiating gait. Three months after onset of symptoms, infiltrating ductal carcinoma of the breast, metastatic to liver and lymph nodes, was diagnosed and treated briefly with cyclophosphamide, methotrexate, and 5-flourouracil (5FU). Severe symmetric action and postural tremor with a myoclonic component developed, with minimal rest tremor, severe dysarthria and dysphagia, small-stepped and slightly ataxic gait progressing to a bedbound state, and severe widespread dystonic posturing. The latter began as a typical parkinsonian posture of trunk and upper extremities and progressed to a fixed and painful flexion of the elbows and wrists and extension of fingers and neck. Sinemet, anticholinergics, baclofen, diazepam, and plasmapheresis gave no benefit. The patient died of complications of immobility 5 months after neurologic symptom onset. Autopsy revealed many pigment-laden macrophages in substantia nigra and moderate loss of pigmented neurons. Inflammation, Lewy bodies, and tumor were absent. Cerebellar Purkinje cells were moderately depleted. Mild neuronal loss and gliosis were present in globus pallidus and cerebellar cortex. Stains for anti-human IgG, IgM, kappa, and lambda were negative. This, to our knowledge, is the first report of paraneoplastic degeneration of substantia nigra or paraneoplastic parkinsonism.

  20. Nerve Regenerative Effects of GABA-B Ligands in a Model of Neuropathic Pain

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    Valerio Magnaghi

    2014-01-01

    Full Text Available Neuropathic pain arises as a direct consequence of a lesion or disease affecting the peripheral somatosensory system. It may be associated with allodynia and increased pain sensitivity. Few studies correlated neuropathic pain with nerve morphology and myelin proteins expression. Our aim was to test if neuropathic pain is related to nerve degeneration, speculating whether the modulation of peripheral GABA-B receptors may promote nerve regeneration and decrease neuropathic pain. We used the partial sciatic ligation- (PSL- induced neuropathic model. The biochemical, morphological, and behavioural outcomes of sciatic nerve were analysed following GABA-B ligands treatments. Simultaneous 7-days coadministration of baclofen (10 mg/kg and CGP56433 (3 mg/kg alters tactile hypersensitivity. Concomitantly, specific changes of peripheral nerve morphology, nerve structure, and myelin proteins (P0 and PMP22 expression were observed. Nerve macrophage recruitment decreased and step coordination was improved. The PSL-induced changes in nociception correlate with altered nerve morphology and myelin protein expression. Peripheral synergic effects, via GABA-B receptor activation, promote nerve regeneration and likely ameliorate neuropathic pain.

  1. GABAergic responses of mammalian ependymal cells in the central canal neurogenic niche of the postnatal spinal cord.

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    Corns, Laura F; Deuchars, Jim; Deuchars, Susan A

    2013-10-11

    The area surrounding the central canal of the postnatal mammalian spinal cord is a highly plastic region that exhibits many similarities to other postnatal neurogenic niches, such as the subventricular zone. Within this region, ependymal cells have been identified as neural stem cells however very little is known about their properties and how the local environment, including neurotransmitters, is capable of affecting them. The neurotransmitter GABA is present around the central canal and is known to affect cells within other postnatal neurogenic niches. This study used whole cell patch clamp electrophysiology and intracellular dye-loading in in vitro Wistar rat spinal cord slices to characterise ependymal cells and their ability to respond to GABA. Ependymal cells were defined by their passive response properties and low input resistances. Extensive dye-coupling was observed between ependymal cells; this was confirmed as gap junction coupling using the gap junction blocker, 18β-glycyrrhetinic acid, which significantly increased the input resistance of ependymal cells. GABA depolarised all ependymal cells tested; the partial antagonism of this response by bicuculline and gabazine indicates that GABA(A) receptors contribute to this response. A lack of effect by baclofen suggests that GABA(B) receptors do not contribute to the GABAergic response. The ability of ependymal cells to respond to GABA suggests that GABA could be capable of influencing the proliferation and differentiation of cells within the neurogenic niche of the postnatal spinal cord.

  2. Therapeutic electrical stimulation for spasticity: quantitative gait analysis.

    Science.gov (United States)

    Pease, W S

    1998-01-01

    Improvement in motor function following electrical stimulation is related to strengthening of the stimulated spastic muscle and inhibition of the antagonist. A 26-year-old man with familial spastic paraparesis presented with gait dysfunction and bilateral lower limb spastic muscle tone. Clinically, muscle strength and sensation were normal. He was considered appropriate for a trial of therapeutic electrical stimulation following failed trials of physical therapy and baclofen. No other treatment was used concurrent with the electrical stimulation. Before treatment, quantitative gait analysis revealed 63% of normal velocity and a crouched gait pattern, associated with excessive electromyographic activity in the hamstrings and gastrocnemius muscles. Based on these findings, bilateral stimulation of the quadriceps and anterior compartment musculature was performed two to three times per week for three months. Repeat gait analysis was conducted three weeks after the cessation of stimulation treatment. A 27% increase in velocity was noted associated with an increase in both cadence and right step length. Right hip and bilateral knee stance motion returned to normal (rather than "crouched"). No change in the timing of dynamic electromyographic activity was seen. These findings suggest a role for the use of electrical stimulation for rehabilitation of spasticity. The specific mechanism of this improvement remains uncertain.

  3. Gamma-butyrolactone (GBL) disruption of passive avoidance learning in the day-old chick appears to be due to its effect on GABAB not gamma-hydroxybutyric [corrected] acid (GHB) receptors.

    Science.gov (United States)

    Sherry, Joanne M; Hazi, Agnes; Hale, Mathew W; Milsome, Sarah L; Crowe, Simon F

    2009-02-11

    Gamma-butyrolactone (GBL) is a prodrug to gamma-hydroxybutyric acid (GHB) and metabolises to GHB when ingested. Discrimination stimulus studies report generalisation of effects of GHB to GBL. While amnesia is one of the most commonly reported symptoms of GHB's ingestion in human users, as yet few studies have examined this effect. Although an endogenous GHB specific receptor is present in the brain, several studies have indicated that the clinical effects of exogenous doses of GBL/GHB are due to its action on GABA(B) receptors rather than on the GHB receptor. In this series of studies, New Hampshire x White leghorn cockerels were trained using a modified version of the passive avoidance learning task. Subcutaneous injections of GBL induced a memory deficit by 10 min post-training, which persisted for at least 24 h. No effect on memory was seen with administration of the specific GHB agonist NCS-356 (gamma-p-chlorophenyl-trans-4-hydroxycrotonate). The GBL-induced memory deficit appeared similar to the deficit produced by baclofen, where the antagonist facilitated learning. Additionally, GBL-induced memory deficit was ameliorated by application of a GABA(B) antagonist. The results support the hypothesis that GBL exerts its influence on memory via the GABA(B) receptor rather than by the specific GHB receptor.

  4. A larval zebrafish model of bipolar disorder as a screening platform for neuro-therapeutics.

    Science.gov (United States)

    Ellis, Lee David; Soanes, Kelly Howard

    2012-08-01

    Modelling neurological diseases has proven extraordinarily difficult due to the phenotypic complexity of each disorder. The zebrafish has become a useful model system with which to study abnormal neurological and behavioural activity and holds promise as a model of human disease. While most of the disease modelling using zebrafish has made use of adults, larvae hold tremendous promise for the high-throughput screening of potential therapeutics. The further development of larval disease models will strengthen their ability to contribute to the drug screening process. Here we have used zebrafish larvae to model the symptoms of bipolar disorder by treating larvae with sub-convulsive concentrations of the GABA antagonist pentylenetetrazol (PTZ). A number of therapeutics that act on different targets, in addition to those that have been used to treat bipolar disorder, were tested against this model to assess its predictive value. Carbamazepine, valproic acid, baclofen and honokiol, were found to oppose various aspects of the PTZ-induced changes in activity. Lidocaine and haloperidol exacerbated the PTZ-induced activity changes and sulpiride had no effect. By comparing the degree of phenotypic rescue with the mechanism of action of each therapeutic we have shown that the low-concentration PTZ model can produce a number of intermediate phenotypes that model symptoms of bipolar disorder, may be useful in modelling other disease states, and will help predict the efficacy of novel therapeutics.

  5. Actions of insecticides on the insect GABA receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Bermudez, I.; Hawkins, C.A.; Taylor, A.M.; Beadle, D.J. (School of Biological and Molecular Sciences, Oxford Polytechnic, Headington, Oxford (England))

    1991-01-01

    The actions of insecticides on the insect gamma-aminobutyric acid (GABA) receptor were investigated using (35S)t-butylbicyclophosphorothionate (( 35S)TBPS) binding and voltage-clamp techniques. Specific binding of (35S)TBPS to a membrane homogenate derived from the brain of Locusta migratoria locusts is characterised by a Kd value of 79.3 {plus minus} 2.9 nM and a Bmax value of 1770 {plus minus} 40 fmol/mg protein. (35S)TBPS binding is inhibited by mM concentrations of barbiturates and benzodiazepines. In contrast dieldrin, ivermectin, lindane, picrotoxin and TBPS are inhibitors of (35S)TBPS binding at the nanomolar range. Bicuculline, baclofen and pyrethroid insecticides have no effect on (35S)TBPS binding. These results are similar to those obtained in electrophysiological studies of the current elicited by GABA in both Locusta and Periplaneta americana central neurones. Noise analysis of the effects of lindane, TBPS, dieldrin and picrotoxin on the cockroach GABA responses reveals that these compounds decrease the variance of the GABA-induced current but have no effect on its mean open time. All these compounds, with the exception of dieldrin, significantly decrease the conductance of GABA-evoked single current.

  6. Behavioral and Biochemical Evidences for Antidepressant-Like Activity of Celastrus Paniculatus Seed Oil in Mice

    Science.gov (United States)

    Valecha, Rekha; Dhingra, Dinesh

    2016-01-01

    Introduction: Celastrus paniculatus seed oil, commonly known as Malkangni or Jyotishmati, was in use from time immemorial to treat brain related disorders. Celastrus paniculatus seed oil has significant antidepressant-like activity in chronic unpredictable stressed mice. The present study was undertaken to evaluate the antidepressant-like effect of Celastrus paniculatus seed oil in unstressed mice and to explore its mechanism of action. Methods: The seed oil (50, 100, and 200 mg/kg, PO) and fluoxetine per se were administered for 14 successive days to Swiss young albino mice. On the 14th day, 60 min after drug administration, animals were subjected to Tail Suspension Test (TST) and Forced Swim Test (FST). The mechanism of action was also studied. Results: The oil significantly decreased immobility period of mice in both tail suspension test and forced swim test, indicating its significant antidepressant-like activity. The efficacy was found to be comparable to fluoxetine (PSulpiride (selective D2-receptor antagonist), p-CPA (tryptophan hydroxylase inhibitor), and baclofen (GABAB agonist) significantly attenuated the oil-induced antidepressant-like effect, when assessed during TST. Discussion: Celastrus paniculatus seed oil produced significant antidepressant-like effect in mice possibly through interaction with dopamine D2, serotonergic, and GABAB receptors; as well as inhibition of MAO–A activity and decrease in plasma corticosterone levels. PMID:27303599

  7. EAT PINEAPPLE A DAY TO KEEP DEPRESSION AT BAY

    Directory of Open Access Journals (Sweden)

    Parle Milind

    2010-12-01

    Full Text Available Pineapple, a juicy and tasty fruit, belonging to family Bromeliaceae is scientifically known as Ananas cosmosus. The Pineapples are traditionally used as a blood purifier, to aid digestion, for gastro-intestinal disorders, diseases of the larynx and pharynx, as a mild antiseptic and to treat diabetes. There are no reports in literature pertaining to CNS actions of Ananas cosmosus fruit. In the light of above, the present study was undertaken to test the antidepressant potential of Ananas cosmosus fruit juice. Ananas cosmosus juice (ACJ was administered at various concentrations ranging from 5% to 20% v/v to Swiss albino mice for 15 days and wistar rats for 8 successive days. The antidepressant activity was measured using forced swim test (FST, tail suspension test (TST and reserpine induced hypothermia. The efficacy of Pineapple juice was compared with standard anti-depressant agents viz: fluoxetine (20 mg/kg and imipramine (15 mg/kg. The results showed that Pineapple juice significantly decreased immobility time in both FST and TST models. It also reversed the hypothermia induced by reserpine. The efficacy of Pineapple juice was found to be comparable to fluoxetine and imipramine. Prazosin, sulpiride, baclofen and p-CPA antagonized the antidepressant effect of Pineapple juice in tail suspension test. Furthermore, Ananas cosmosus juice inhibited the monoamine oxidase MAO-A and MAO-B activity and reduced significantly malondialdehyde (MDA levels. These findings reveal the anti-depressant potential of Pineapple.

  8. Dissociation and trafficking of rat GABAB receptor heterodimer upon chronic capsaicin stimulation.

    Science.gov (United States)

    Laffray, Sophie; Tan, Kelly; Dulluc, Josette; Bouali-Benazzouz, Rabia; Calver, Andrew R; Nagy, Frédéric; Landry, Marc

    2007-03-01

    Gamma-aminobutyric acid type B receptors (GABAB) are G-protein-coupled receptors that mediate GABAergic inhibition in the brain. Their functional expression is dependent upon the formation of heterodimers between GABAB1 and GABAB2 subunits, a process that occurs within the endoplasmic reticulum. However, the mechanisms that regulate GABAB receptor oligomerization at the plasma membrane remain largely unknown. We first characterized the functional cytoarchitecture of an organotypic co-culture model of rat dorsal root ganglia and spinal cord. Subsequently, we studied the interactions between GABAB subunits after chronic stimulation of sensory fibres with capsaicin. Surface labelling of recombinant proteins showed a decrease in subunit co-localization and GABAB2 labelling, after capsaicin treatment. In these conditions, fluorescence lifetime imaging measurements further demonstrated a loss of interactions between green fluorescent protein-GABAB1b and t-dimer discosoma sp red fluorescent protein-GABAB2 subunits. Finally, we established that the GABAB receptor undergoes clathrin-dependent internalization and rapid recycling to the plasma membrane following activation with baclofen, a GABAB agonist. However, in cultures chronically stimulated with capsaicin, the agonist-induced endocytosis was decreased, reflecting changes in the dimeric state of the receptor. Taken together, our results indicate that the chronic stimulation of sensory fibres can dissociate the GABAB heterodimer and alters its responsiveness to the endogenous ligand. Chronic stimulation thus modulates receptor oligomerization, providing additional levels of control of signalling.

  9. [Case of painful muscle spasm induced by thoracic vertebral fracture: successful treatment with lumbar sympathetic ganglia block].

    Science.gov (United States)

    Shimizu, Fumitaka; Kawai, Motoharu; Koga, Michiaki; Ogasawara, Jun-ichi; Negoro, Kiyoshi; Kanda, Takashi

    2008-10-01

    We report a 70-year-old man, who developed painful involuntary muscle contraction of the left leg after the lumbar discectomy, which exacerbated after a vertebral fracture of Th12. This involuntary movement was accompanied with the abnormal position of left leg simulating triple flexion response, and was induced by active or passive movement of his left knee and foot joints. Several drugs including benzodiazepines and dantrolene were ineffective, although treatment with baclofen or carbamazepine was effective. These findings suggest that hyperexcitability of the anterior horn cells following the disturbance of spinal inhibitory interneurons was involved. Electophysiological studies suggested the disturbance of left lumber nerve roots. The spinal root blocks from L3 to S1 were performed, after which the painful involuntary muscle spasm was resolved. The lumbar sympathetic ganglia block was also effective; suggesting that abnormal afferent neuronal input to spinal cord was caused by the nerve root trauma which triggered the formation of secondary abnormal network in the spine. Lumbar sympathetic ganglia block should be recommended to a therapeutic option for the refractory painful muscle spasm of the leg.

  10. Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

    Science.gov (United States)

    Bansinath, M; Ramabadran, K; Turndorf, H; Shukla, V K

    1991-07-01

    Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

  11. An aggressive approach to limb dystonia: a case report.

    Science.gov (United States)

    Moberg-Wolff, E A

    1998-05-01

    A 15-year-old boy presented with a severe fluctuating foot and ankle dystonia resulting from a basal ganglia insult at the age of 4. This followed an embolic event related to an undiagnosed prolapsed mitral valve. Functionally, the patient was ambulatory with rocker bottom crutches and an ankle-foot orthosis, but there were periods of up to a year when pain and increased dystonic deformity required him to use a wheelchair. A new orthotic was made nearly every month because the orthotist could find no material that would withstand his tone without breaking, yet he could not ambulate without one. Multiple interventions, including biofeedback, contrast baths, stretching and strengthening, oral lioresal (Baclofen), diazepam (Valium), benztropine mesylate (Cogentin), carbidopa-levodopa (Sinemet), carbamazepine (Tegretol), and injections of botulism toxin (BOTOX) were tried, all with minimal effects. Amputation was recommended, based on anatomic and functional considerations. The patient and his family adjusted well to this decision, although not all orthopedists and therapists adjusted easily to the choice. The patient is now functionally independent with a prosthesis and has a normal teenage lifestyle for the first time.

  12. Clonus: definition, mechanism, treatment

    Directory of Open Access Journals (Sweden)

    Ismail Boyraz

    2015-02-01

    Full Text Available Clonus is involuntary and rhythmic muscle contractions caused by a permanent lesion in descending motor neurons. Clonus may be found at the ankle, patella, triceps surae, wrist, jaw, biceps brachii. In general, clonus may occur in any muscle with a frequency of 5-8 Hz and the average period of oscillations of the ankle clonus is approximately 160–200 ms. Plantar flexion (PF comprises 45% of the period, dorsifleksion (DF comprises 55% of the period. The first beat is always longer, with the time shortening in continuing beats and becoming stable in the 4th or 5th period. The exact mechanism of clonus remains unclear. Two different hypotheses have been asserted regarding the development of clonus. The most widely accepted explanation is that hyperactive stretch reflexes in clonus are caused by self-excitation. Another alternative explanation for clonus is central generator activity that arises as a consequence of appropriate peripheral events and produces rhythmic stimulation of the lower motor neurons. The durations of clonus burst were found longer than the durations of Soleus medium-latency reflex (MLR. There is a similarity in their nature, although the speed and cause of the stretch of triceps surae differ in the MLR and the clonus, and there is a sufficient period of time for group II afferents and for other spinal mechanisms to be involved in the clonus, together with Ia afferents. Clonus can be treated by using baclofen, applying cold, botox or phenol injections.

  13. Pain in adults with cerebral palsy: impact and solutions.

    Science.gov (United States)

    Vogtle, Laura K

    2009-10-01

    Studies of health in adults with cerebral palsy (CP) have identified pain as a significant concern. Investigations regarding incidence, intensity, and location in adults with CP found that increasing age and inactivity appeared to be related to pain. Activity and participation in adults with CP seem to be only moderately affected by presence of pain. Various sources of pain have been identified in adults with CP but have not been well studied. These include orthopedic issues, poor bone mineral density and related fractures, dental and jaw problems, and nutrition-related pain. Limited healthcare utilization studies suggest that adults with CP use healthcare services, especially preventative and rehabilitative services less, and do not consult physicians regarding pain. Medication solutions for chronic pain are not well studied. Botulinum toxin and intrathecal baclofen have been demonstrated to minimize pain; however, the impact of other medications needs further investigation. Other interventions for pain include small studies examining the use of biofeedback and exercise. Larger studies are needed to establish effectiveness. In order to prevent future generations of adults with CP from experiencing high levels of pain, environmental sources of pain need more specific study, as do interventions that are affordable and easily accessed.

  14. GABAB receptor trafficking and interacting proteins: targets for the development of highly specific therapeutic strategies to treat neurological disorders?

    Science.gov (United States)

    Benke, Dietmar

    2013-12-01

    GABAB receptors mediate slow inhibitory neurotransmission throughout the central nervous system thereby controlling the excitability of neurons. They have been implicated in numerous neurological disorders making them an attractive drug target. However, due to considerable side effects, the agonist baclofen is so far the only drug on the market targeting GABAB receptors, primarily for the treatment of spasticity. Because GABAB receptors are involved in a variety of brain functions it is rather unlikely to avoid unwanted effects with systemically administered drugs directly addressing ligand binding sites of the receptor. To minimize side effects, it would be desirable to target only those receptors involved in a given pathological state. This commentary discusses the idea that restoring impaired GABAB receptor function in diseased neurons by interfering with receptor-protein interactions may be an approach to specifically target only those receptors involved in the pathological state. Two recently discovered mechanisms that down-regulate the level of functional GABAB receptors most likely contribute to cerebral ischemia and neuropathic pain, respectively. In both mechanisms, small interfering peptides disrupting protein-protein interactions may offer a highly specific means to restore normal receptor function selectively at the site of malfunction. If restored functional GABAB receptor expression in these diseases has beneficial effects, this may serve as a starting point for the development of a highly specific therapeutic interventions. Such an approach is expected to minimize side effects because it promises to leave those GABAB receptors unaffected which are not involved in the dysfunction.

  15. Multidisciplinary View of Alcohol Use Disorder: From a Psychiatric Illness to a Major Liver Disease.

    Science.gov (United States)

    Gitto, Stefano; Golfieri, Lucia; Caputo, Fabio; Grandi, Silvana; Andreone, Pietro

    2016-01-15

    Alcohol use disorder is a significant health problem being a cause of increased morbidity and mortality worldwide. Alcohol-related illness has a relevant economic impact on the society and a negative influence on the life of patients and their family members. Psychosocial support might be useful in the management of people affected by alcohol use disorder since psychiatric and pharmaceutical approaches show some limits. In fact, many drugs are accessible for the treatment of alcohol disorder, but only Baclofen is functional as an anti-craving drug in patients with advanced liver disease. The alcohol-related liver damage represents the most frequent cause of advanced liver disease in Europe, and it is the main cause of death among adults with high alcohol consumption. The multidisciplinary action of clinical-psychologists, psychiatrics and hepatologists, is essential in the management of patients with alcohol liver disease especially in the case of liver transplantation. In general, the multidisciplinary approach is necessary in prevention, in framing patients and in the treatment. More resources should be used in prevention and research with the main aim of decreasing the harmful alcohol consumption.

  16. Comparison of in vitro cell models in predicting in vivo brain entry of drugs.

    Science.gov (United States)

    Hakkarainen, Jenni J; Jalkanen, Aaro J; Kääriäinen, Tiina M; Keski-Rahkonen, Pekka; Venäläinen, Tetta; Hokkanen, Juho; Mönkkönen, Jukka; Suhonen, Marjukka; Forsberg, Markus M

    2010-12-15

    Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.99, Caco-2 r=0.91 and MDCKII-MDR1 r=0.85). Despite of the substantial differences in the absolute in vitro P(app) values and regardless of the method used (side-by-side vs. filter insert system), the capability of the in vitro models to rank order drugs was similar. By this approach, thus, the additional value offered by the true endothelial cell model (BBMEC) remains obscure. The present results also highlight the need of both in vitro as well as in vivo methods in characterization of blood-brain barrier passage of new drug candidates.

  17. Antidepressant activity of Ceratonia siliqua L. fruit extract, a source of polyphenols.

    Science.gov (United States)

    Agrawal, Ashok; Mohan, Mahalaxmi; Kasture, Sanjay; Foddis, Caterina; Frau, Maria Assunta; Loi, Maria Cecilia; Maxia, Andrea

    2011-02-01

    A previous study from our laboratory has shown the facilitatory effect of Ceratonia siliqua L. (Fabaceae) on the dopaminergic function. This study investigates the involvement of monoamines in the antidepressant activity of the total polyphenol content of Ceratonia siliqua extract (CS) in mice using a tail suspension test (TST) and forced swim test (FST). The immobility time in the TST and FST were significantly reduced by CS (25 and 50 mg kg(-1), i.p.). The extract considerably attenuated the duration of immobility induced by prazosin (62.5 µg kg(-1), i.p., an α-adrenoceptor antagonist) and eticlopride (0.1 µg kg(-1), i.p., a classical D2-like dopamine receptor antagonist) in both TST and FST, whereas the extract could not modify the immobility in mice treated with p-chlorophenylalanine (100 mg kg(-1), i.p., ×3 days; an inhibitor of serotonin synthesis) and baclofen (10 mg kg(-1), i.p., GABAB agonist). This suggests that the antidepressant effect of CS is mediated by dopamine and noradrenaline.

  18. The surgical management of spasticity.

    Science.gov (United States)

    Lazorthes, Y; Sol, J-C; Sallerin, B; Verdié, J-C

    2002-05-01

    Neurosurgery is only considered for severe spasticity following the failure of noninvasive management (adequate medical and physical therapy). The patients are carefully selected, based on rigorous multidisciplinary clinical assessment. In this we evaluate the contribution of the spasticity to the disability and any residual voluntary motor function. The goals for each patient are: (a) improvement of function and autonomy; (b) control of pain; and (c) prevention of orthopaedic disorders. To achieve these objectives, the surgical procedure must be selective and reduce the excessive hypertonia without suppressing useful muscle tone and limb functions. The surgical procedures are: (1) Classical neuro-ablative techniques (peripheral neurotomies, dorsal rhizotomies) and their modern modifications using microsurgery and intra-operative neural stimulation (dorsal root entry zone: DREZotomy). These techniques are destructive and irreversible, with the reduced muscle tone reflecting the nerve topography. It is mainly indicated when patients have localized spasticity without useful mobility. (2) Conservative techniques based on a neurophysiological control mechanism. These procedures are totally reversible. The methods involve chronic neurostimulation of the spinal cord or the cerebellum. There are only a few patients for whom this is indicated. Conversely, chronic intrathecal administration of baclofen, using an implantable pump, is well established in the treatment of diffuse spasticity of spinal origin. From reports in the literature, we critically review the respective indications in terms of function, clinical progression and the topographic extent of the spasticity.

  19. Evidences for the involvement of monoaminergic and GABAergic systems in antidepressant-like activity of Tinospora cordifolia in mice

    Directory of Open Access Journals (Sweden)

    Dhingra D

    2008-01-01

    Full Text Available The present study was taken up to investigate the effect of petroleum ether extract of Tinospora cordifolia (Wild. Miers, on depression in mice. The extract (50, 100 and 200 mg/kg, p.o. was administered for 14 successive days to Swiss young albino mice (either sex and evaluated for antidepressant-like activity using tail suspension test and forced swim test. Petroleum ether extract at all three doses produced significant antidepressant-like effect in tail suspension test as well as in forced swim test and their efficacies were found to be comparable to imipramine (15 mg/kg, p.o. and sertraline (20 mg/kg, p.o.. The extract at a dose of 50 mg/kg showed most potent effect and did not show any significant change in locomotor functions of mice as compared to control. The antidepressant-like effect of the extract was significantly reversed by pretreatment of animals with prazosin (a α1 -adrenoceptor antagonist, sulpiride (a selective dopamine D 2 -receptor antagonist, p-CPA (a serotonin synthesis inhibitor and baclofen (GABA-B agonist, when tested in tail suspension test. Moreover, petroleum ether extract also reduced the mouse whole brain monoamine oxidase (MAO-A and MAO-B activities as compared to control, resulting in increase in the levels of brain monoamines. Therefore, the extract may have potential therapeutic value for the management of depressive disorders.

  20. 巴氯芬并奥美拉唑治疗NERD的疗效观察

    Institute of Scientific and Technical Information of China (English)

    李新练

    2013-01-01

    目的 探讨巴氯芬(Baclofen)并奥美拉唑治疗非糜烂性胃食管反流病(NERD)的疗效.方法 96例患者随机分为治疗组50例和对照组46例.治疗组为巴氯芬并奥美拉唑治疗,对照组为奥美拉唑治疗,观察2组临床症状缓解和食管PH值、胃镜检查情况.结果 治疗组总有效率84%(42/50)均明显高于对照组58.7%(27/46),差异有统计学意义(P<0.05).结论 巴氯芬并奥美拉唑治疗NERD与对照组比较疗效满意,有一定的临床价值.

  1. Cardiovascular effects of lateral intracerebroventricular injection of L-securinine%侧脑室注射一叶萩碱的心血管效应及作用机制

    Institute of Scientific and Technical Information of China (English)

    赵晓燕; 蒋正尧; 彭建中

    2000-01-01

    在麻醉大鼠侧脑室注射左旋一叶萩碱(L-Sec), 记录动脉血压(AP)、心率(HR)及肾交感神经放电(RSND), 观察前脑室周系统GABA能紧张性活动改变引起的心血管效应.结果如下: (1) L-Sec可引起RSND增加、AP升高和HR加快, 并呈一定剂量-效应关系; 但L-Sec作用明显弱于bicuculline (Bic).(2) L-Sec 既能拮抗muscimol (Mus), 又能拮抗baclofen (Bac)引起的交感抑制和降压反应.上述结果提示: (1) 前脑室周部位存在GABA能抑制机制, 对交感心血管系统具有紧张性抑制作用, L-Sec解除了这种抑制, 使交感神经系统传出活动增强, 因而产生升压作用.(2) L-Sec可能是一种非选择性的GABA受体拮抗剂.

  2. Effect of Gamma Aminobutyric Acid B Receptor on Brain Damage Induced by Recurrent Febrile Seizures%γ-氨基丁酸B受体在反复热性惊厥脑损伤中的作用

    Institute of Scientific and Technical Information of China (English)

    韩颖; 秦炯; 卜定方; 常杏芝; 杨志仙

    2005-01-01

    目的探讨γ-氨基丁酸B受体(γ-aminobutyric acid B receptor,GABABR)对反复热性惊厥(febrile seizures,FS)脑损伤的影响.方法SD大鼠随机分为对照组、FS组、FS+氯苯氨丁酸(baclofen)组、FS+法克罗芬(phaclofen)组.采用热水浴诱导大鼠FS,隔日诱导1次,共10次.记录大鼠惊厥潜伏期、持续时间及强度;用原位杂交和免疫组织化学方法分别观察c-fos基因和Fos蛋白表达情况.结果与FS组相比,FS+baclofen组大鼠惊厥潜伏期延长、惊厥持续时间缩短、惊厥强度减轻;而FS+phaclofen组大鼠惊厥潜伏期缩短、惊厥持续时间延长、惊厥强度加重.baclofen干预使c-fos基因和Fos蛋白表达降低,而phaclofen 干预使其表达增强.结论应用GABABR激动剂baclofen和抑制剂phaclofen干预研究表明,GABABR与热性惊厥脑损伤的发生、发展密切相关.

  3. 鞘内注射巴氯酚治疗痉挛型脑瘫的临床应用

    Institute of Scientific and Technical Information of China (English)

    刘建军; 吴卫红; 纪树荣

    2003-01-01

    @@ 脑瘫是造成儿童残疾的重要疾患之一.尽管在过去20年中围产期医学得到了发展,但脑瘫(cerebral palsy,CP)的发病率没有明显改变,仍在1.5‰-2.5‰左右[1].脑瘫患儿60%-80%是痉挛型,如何缓解痉挛一直是康复医师所面临的重要课题.过去只重视痉挛后果的治疗,现在开始重视痉挛本身的治疗[2],出现了选择性脊神经后根切除术、肉毒毒素注射[3]等方法.Penn等人于1984年首次报道了鞘内注射巴氯酚(intrathecal baclofen,ITB)缓解痉挛[3],开辟了一条治疗痉挛的新路.后来发展为将巴氯酚泵植入患者皮下,实现了连续给药,长时间缓解痉挛.

  4. Neutral amino acid transport across brain microvessel endothelial cell monolayers

    Energy Technology Data Exchange (ETDEWEB)

    Audus, K.L.; Borchardt, R.T.

    1986-03-01

    Brain microvessel endothelial cells (BMEC) which form the blood-brain barrier (BBB) possess an amino acid carrier specific for large neutral amino acids (LNAA). The carrier is important for facilitating the delivery of nutrient LNAA's and centrally acting drugs that are LNAA's, to the brain. Bovine BMEC's were isolated and grown up to complete monolayers on regenerated cellulose-membranes in primary culture. To study the transendothelial transport of leucine, the monolayers were placed in a side-by-side diffusion cell, and transport across the monolayers followed with (/sup 3/H)-leucine. The transendothelial transport of leucine in this in vitro model was determined to be bidirectional, and time-, temperature-, and concentration-dependent. The transport of leucine was saturable and the apparent K/sub m/ and V/sub max/, 0.18 mM and 6.3 nmol/mg/min, respectively. Other LNAA's, including the centrally acting drugs, ..cap alpha..-methyldopa, L-DOPA, ..cap alpha..-methyl-tyrosine, and baclofen, inhibited leucine transport. The leucine carrier was also found to be stereospecific and not sensitive to inhibitors of active transport. These results are consistent with previous in vitro and in vivo studies. Primary cultures of BMEC's appear to be a potentially important tool for investigating at the cellular level, the transport mechanisms of the BBB.

  5. Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A

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    Mathew Jobin

    2012-02-01

    Full Text Available Abstact Background Gamma amino butyric acid (GABA, the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue. Methods In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated. Results Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P Aά1, GABAAγ, GABAAδ, GABAB and GAD where down regulated (P Aά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance. Conclusions Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management.

  6. Multidisciplinary View of Alcohol Use Disorder: From a Psychiatric Illness to a Major Liver Disease

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    Stefano Gitto

    2016-01-01

    Full Text Available Alcohol use disorder is a significant health problem being a cause of increased morbidity and mortality worldwide. Alcohol-related illness has a relevant economic impact on the society and a negative influence on the life of patients and their family members. Psychosocial support might be useful in the management of people affected by alcohol use disorder since psychiatric and pharmaceutical approaches show some limits. In fact, many drugs are accessible for the treatment of alcohol disorder, but only Baclofen is functional as an anti-craving drug in patients with advanced liver disease. The alcohol-related liver damage represents the most frequent cause of advanced liver disease in Europe, and it is the main cause of death among adults with high alcohol consumption. The multidisciplinary action of clinical-psychologists, psychiatrics and hepatologists, is essential in the management of patients with alcohol liver disease especially in the case of liver transplantation. In general, the multidisciplinary approach is necessary in prevention, in framing patients and in the treatment. More resources should be used in prevention and research with the main aim of decreasing the harmful alcohol consumption.

  7. GABA Receptor Agonists Rescued Cortical Neurons from Oxygen-Glucose Deprivation%GABA受体激动剂对氧-葡萄糖剥夺诱导皮层神经元死亡的保护作用

    Institute of Scientific and Technical Information of China (English)

    吴翠莹; 李树基; 高天明

    2010-01-01

    目的:研究GABA受体激动剂对氧-葡萄糖剥夺诱导皮层神经元死亡的保护作用.方法: 培养12d的皮层神经元更换为Earle's 平衡盐溶液(Earle's balanced salts ,EBSS)后置于37℃三气缺氧(N2:CO2:O2= 94%:5%:1%)培养箱内培养,4h后恢复正常条件培养,同时在培养液内加入GABA A受体和B受体激动剂作用24h,用Hoechst33342/PI的染色方法检测其死亡情况.结果: GABA A受体激动剂(muscimol)和GABA B受体激动剂(baclofen)均分别能显著降低神经细胞死亡率49.9%和35.3%. 结论: GABA A受体激动剂和B受体激动剂对氧-葡萄糖剥夺诱导的皮层神经元死亡均有显著的保护作用.

  8. Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Supavilai, P.; Karobath, M.

    1985-02-04

    GABA, THIP and muscimol enhance spontaneous and inhibit electrically induced release of tritium labelled compounds from rat striatal slices which have been pre-labelled with /sup 3/H-choline. Baclofen is inactive in this model. Muscimol can inhibit electrically induced release of tritiated material by approximately 75% with half maximal effects at 2 ..mu..M. The response to muscimol can be blocked by the GABA antagonists bicuculline methobromide, picrotoxin, anisatin, R 5135 and CPTBO (cyclopentylbicyclophosphate). Drugs which act on the benzodiazepine receptor (BR) require the presence of muscimol to be effective and they modulate the effects of muscimol in a bidirectional manner. Thus BR agonists enhance and inverse BR agonists attenuate the inhibitory effects of muscimol on electrically induced release. Ro15-1788, a BR antagonist, does not modulate the inhibitory effects of muscimol but antagonizes the actions of clonazepam, a BR agonist, and of DMCM, an inverse BR agonist. These results demonstrate that a GABA/benzodiazepine receptor complex can modulate acetylcholine release from rat striatal slices in vitro. 24 references, 3 figures, 5 table.

  9. Reduction of GABA/sub B/ receptor binding induced by climbing fiber degeneration in the rat cerebellum

    Energy Technology Data Exchange (ETDEWEB)

    Kato, K.; Fukuda, H.

    1985-07-22

    When the rat cerebellar climbing fibers degenerated, as induced by lesioning the inferior olive with 3-acetylpyridine (3-AP), GABA/sub B/ receptor binding determined with /sup 3/H-(+/-)baclofen was reduced in the cerebellum but not in the cerebral cortex of rats. Computer analysis of saturation data revealed two components of the binding sites, and indicated that decrease of the binding in the cerebellum was due to reduction in receptor density, mainly of the high-affinity sites, the B/sub max/ of which was reduced to one-third that in the control animals. In vitro treatment with 3-AP, of the membranes prepared from either the cerebellum or the cerebral cortex, induced no alteration in the binding sites, thereby indicating that the alteration of GABA/sub B/ sites induced by in vivo treatment with 3-AP is not due to a direct action of 3-AP on the receptor. GABA/sub A/ and benzodiazepine receptor binding labelled with /sup 3/H-muscimol and /sup 3/H-diazepam, respectively, in both of brain regions was not affected by destruction of the inferior olive. These results provide evidence that some of the GABA/sub B/ sites but neither GABA/sub A/ nor benzodiazepine receptors in the cerebellum are located at the climbing fiber terminals. 28 references, 4 figures, 2 tables.

  10. CXCL12 chemokine and GABA neurotransmitter systems crosstalk and their putative roles

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    Guyon eAlice

    2014-04-01

    Full Text Available Since CXCL12 and its receptors, CXCR4 and CXCR7, have been found in the brain, the role of this chemokine has been expanded from chemoattractant in the immune system to neuromodulatory in the brain. Several pieces of evidence suggest that this chemokine system could crosstalk with the GABAergic system, known to be the main inhibitory neurotransmitter system in the brain. Indeed, GABA and CXCL12 as well as their receptors are colocalized in many cell types including neurons and there are several examples in which these two systems interact. Several mechanisms can be proposed to explain how these systems interact, including receptor-receptor interactions, crosstalk at the level of second messenger cascades, or direct pharmacological interactions, as GABA and GABAB receptor agonists/antagonists have been shown to be allosteric modulators of CXCR4.The interplay between CXCL12/CXCR4-CXCR7 and GABA/GABAA-GABAB receptors systems could have many physiological implications in neurotransmission, cancer and inflammation. In addition, the GABAB agonist baclofen is currently used in medicine to treat spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis and other disorders. More recently it has also been used in the treatment of alcohol dependence and withdrawal. The allosteric effects of this agent on CXCR4 could contribute to these beneficial effects or at the opposite, to its side effects.

  11. GABAB receptor subunit GB1 at the cell surface independently activates ERK1/2 through IGF-1R transactivation.

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    Guillaume A Baloucoune

    Full Text Available BACKGROUND: Functional GABA(B receptor is believed to require hetero-dimerization between GABA(B1 (GB1 and GABA(B2 (GB2 subunits. The GB1 extracellular domain is required for ligand binding, and the GB2 trans-membrane domain is responsible for coupling to G proteins. Atypical GABA(B receptor responses observed in GB2-deficient mice suggested that GB1 may have activity in the absence of GB2. However the underlying mechanisms remain poorly characterized. METHODOLOGY/PRINCIPAL FINDINGS: Here, by using cells overexpressing a GB1 mutant (GB1asa with the ability to translocate to the cell surface in the absence of GB2, we show that GABA(B receptor agonists, such as GABA and Baclofen, can induce ERK1/2 phosphorylation in the absence of GB2. Furthermore, we demonstrate that GB1asa induces ERK1/2 phosphorylation through Gi/o proteins and PLC dependent IGF-1R transactivation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that GB1 may form a functional receptor at the cell surface in the absence of GB2.

  12. A functional assay to measure postsynaptic gamma-aminobutyric acidB responses in cultured spinal cord neurons: Heterologous regulation of the same K+ channel

    Energy Technology Data Exchange (ETDEWEB)

    Kamatchi, G.L.; Ticku, M.K. (Univ. of Texas Health Science Center, San Antonio (USA))

    1991-02-01

    The stimulation of postsynaptic gamma-aminobutyric acid (GABA)B receptors leads to slow inhibitory postsynaptic potentials due to the influx of K(+)-ions. This was studied biochemically, in vitro in mammalian cultured spinal cord neurons by using 86Rb as a substitute for K+. (-)-Baclofen, a GABAB receptor agonist, produced a concentration-dependent increase in the 86Rb-influx. This effect was stereospecific and blocked by GABAB receptor antagonists like CGP 35 348 (3-aminopropyl-diethoxymethyl-phosphonic acid) and phaclofen. Apart from the GABAB receptors, both adenosine via adenosine1 receptors and 5-hydroxytryptamine (5-HT) via 5-HT1 alpha agonists also increased the 86Rb-influx. These agonists failed to show any additivity between them when they were combined in their maximal concentration. In addition, their effect was antagonized specifically by their respective antagonists without influencing the others. These findings suggest the presence of GABAB, adenosine1 and 5-HT1 alpha receptors in the cultured spinal cord neurons, which exhibit a heterologous regulation of the same K(+)-channel. The effect of these agonists were antagonized by phorbol 12,13-didecanoate, an activator of protein kinase C, and pretreatment with pertussis toxin. This suggests that these agonists by acting on their own receptors converge on the same K(+)-channel through the Gi/Go proteins. In summary, we have developed a biochemical functional assay for studying and characterizing GABAB synaptic pharmacology in vitro, using spinal cord neurons.

  13. Regional selectivity of a gamma-aminobutyric acid-induced (/sup 3/H)acetylcholine release sensitive to inhibitors of gamma-aminobutyric acid uptake

    Energy Technology Data Exchange (ETDEWEB)

    Bonanno, G.; Raiteri, M.

    1987-05-01

    The effects of gamma-aminobutyric acid (GABA) on the release of (/sup 3/H)acetylcholine ((/sup 3/H)ACh) were studied in synaptosomes prepared from rat hippocampus, cerebral cortex, hypothalamus, and striatum and prelabelled with (/sup 3/H)choline. When synaptosomes were exposed in superfusion to exogenous GABA (0.01-0.3 mM) the basal release of newly synthesized (/sup 3/H)ACh was increased in a concentration-dependent way in hippocampus, cortex, and hypothalamus nerve endings. In contrast, the release of (/sup 3/H)ACh was not significantly affected by GABA in striatal synaptosomes. The effect of GABA was not antagonized significantly by bicuculline or picrotoxin. Muscimol caused only a slight not significant increase of (/sup 3/H)ACh release when tested at 0.3 mM whereas, at this concentration, (-)-baclofen was totally inactive. The GABA-induced release of (/sup 3/H)ACh was counteracted by SKF 89976A, SKF 100561, and SKF 100330A, three strong and selective GABA uptake inhibitors. The data suggest that, in selective areas of the rat brain, GABA causes release of (/sup 3/H)ACh following penetration into cholinergic nerve terminals through a GABA transport system.

  14. Differential Neural Responses Underlying the Inhibition of the Startle Response by Pre-Pulses or Gaps in Mice

    Science.gov (United States)

    Moreno-Paublete, Rocio; Canlon, Barbara; Cederroth, Christopher R.

    2017-01-01

    Gap pre-pulse inhibition of the acoustic startle (GPIAS) is a behavioral paradigm used for inferring the presence of tinnitus in animal models as well as humans. In contrast to pre-pulse inhibition (PPI), the neural circuitry controlling GPIAS is poorly understood. To increase our knowledge on GPIAS, a comparative study with PPI was performed in mice combining these behavioral tests and c-Fos activity mapping in brain areas involved in the inhibition of the acoustic startle reflex (ASR). Both pre-pulses and gaps efficiently inhibited the ASR and abolished the induction of c-Fos in the pontine reticular nucleus. Differential c-Fos activation was found between PPI and GPIAS in the forebrain whereby PPI activated the lateral globus pallidus and GPIAS activated the primary auditory cortex. Thus, different neural maps are regulating the inhibition of the startle response by pre-pulses or gaps. To further investigate this differential response to PPI and GPIAS, we pharmacologically disrupted PPI and GPIAS with D-amphetamine or Dizocilpine (MK-801) to target dopamine efflux and to block NMDA receptors, respectively. Both D-amp and MK-801 efficiently decreased PPI and GPIAS. We administered Baclofen, an agonist GABAB receptor, but failed to detect any robust rescue of the effects of D-amp and MK-801 suggesting that PPI and GPIAS are GABAB-independent. These novel findings demonstrate that the inhibition of the ASR by pre-pulses or gaps is orchestrated by different neural pathways. PMID:28239338

  15. Selectivity Enhancement in Molecularly Imprinted Polymers for Binding of Bisphenol A

    Directory of Open Access Journals (Sweden)

    Noof A. Alenazi

    2016-10-01

    Full Text Available Bisphenol A (BPA is an estrogen-mimicking chemical that can be selectively detected in water using a chemical sensor based on molecularly imprinted polymers (MIPs. However, the utility of BPA-MIPs in sensor applications is limited by the presence of non-specific binding sites. This study explored a dual approach to eliminating these sites: optimizing the molar ratio of the template (bisphenol A to functional monomer (methacrylic acid to cross-linker (ethylene glycol dimethacrylate, and esterifying the carboxylic acid residues outside of specific binding sites by treatment with diazomethane. The binding selectivity of treated MIPs and non-treated MIPs for BPA and several potential interferents was compared by capillary electrophoresis with ultraviolet detection. Baclofen, diclofenac and metformin were demonstrated to be good model interferents to test all MIPs for selective binding of BPA. Treated MIPs demonstrated a significant decrease in binding of the interferents while offering high selectivity toward BPA. These results demonstrate that conventional optimization of the molar ratio, together with advanced esterification of non-specific binding sites, effectively minimizes the residual binding of interferents with MIPs to facilitate BPA sensing.

  16. Regulation of (/sup 3/H)GABA release from strips of guinea pig urinary bladder

    Energy Technology Data Exchange (ETDEWEB)

    Shirakawa, J.; Taniyama, K.; Iwai, S.; Tanaka, C.

    1988-12-01

    The presence of receptors that regulate the release of gamma-aminobutyric acid (GABA) was studied in strips of the guinea pig urinary bladder. GABA (10(-8)-10(-5) M) and muscimol (10(-8)-10(-5) M), but not baclofen (10(-5) M), reduced the Ca2+-dependent, tetrodotoxin-resistant release of (/sup 3/H)GABA evoked by high K+ from the urinary bladder strips preloaded with (/sup 3/H)GABA. The inhibitory effect of muscimol was antagonized by bicuculline and potentiated by diazepam, clonazepam, and pentobarbital sodium. The potentiating effect of clonazepam was antagonized by Ro 15-1788. Acetylcholine (ACh) inhibited the high K+-evoked release of (/sup 3/H)GABA. The inhibitory effect of ACh was antagonized by atropine sulfate and pirenzepine but not by hexamethonium. Norepinephrine (NE) inhibited the evoked release of (/sup 3/H)GABA. The inhibitory effect of NE was mimicked by clonidine, but not by phenylephrine, and was antagonized by yohimbine but not by prazosin. These results provide evidence that the release of GABA from strips of guinea pig urinary bladder is regulated via the bicuculline-sensitive GABAA receptor, M1-muscarinic, and alpha 2-adrenergic receptors.

  17. 选择性脊神经后根切断术解痉治疗的研究进展

    Institute of Scientific and Technical Information of China (English)

    段平国

    2010-01-01

    @@ 脑性瘫痪(cerebral palsy,CP)简称脑瘫,指发生在发育期胎儿或婴儿大脑非进展性缺陷或损害所致的运动及姿势发育持久障碍而引起活动受限的一组综合征[1].痉挛型CP的主要症状就是痉挛,是由牵张反射过度兴奋所致[2].其治疗方法包括物理治疗、鞘内注射巴氯芬(intrathecal baclofen,ITB)、矫形术以及选择性脊神经后根切断术(selective posterior rhizotomy,SPR).其中惟一可持久解痉的方法就是SPR[3].因此,本文就SPR的解痉机制、目前状况、疗效以及并发症等方面的进展进行综述.

  18. Utility of NBD-Cl for the spectrophotometric determination of some skeletal muscle relaxant and antihistaminic drugs

    Science.gov (United States)

    Saleh, Hanaa M.; EL-Henawee, Magda M.; Ragab, Gamal H.; El-Hay, Soad S. Abd

    2007-08-01

    A simple, accurate, precise and sensitive colorimetric method for the determination of some skeletal muscle relaxant drugs, namely orphenadrine citrate ( I), baclofen ( II), antihistaminic drugs as acrivastine ( III) and fexofenadine hydrochloride ( IV) is described. This method is based on the formation of charge transfer complex with 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) in non-aqueous medium. The orange color products were measured at 472, 465, 475 and 469 nm for drugs I, II, III and IV, respectively. The optimization of various experimental conditions was described. Beer's Law was obeyed in the range (2.5-17.5), (5-70), (2.5-25) and (10-50) μg/ml for drugs I, II, III and IV, respectively. The molar absorptivity ( ɛ), sandell sensitivity, detection (LOD) and quantitation limits (LOQ) are calculated. The procedure was favorably applied for determination of certain pharmaceutical dosage forms containing the studied drugs. The obtained results were compared with the official and reported methods. There were no significant differences between proposed, reported and the official methods.

  19. Nootropic and anxiolytic activity of saponins of Albizzia lebbeck leaves.

    Science.gov (United States)

    Une, H D; Sarveiya, V P; Pal, S C; Kasture, V S; Kasture, S B

    2001-01-01

    The effect of saponin containing, n-butanolic fraction (BF), extracted from dried leaves of Albizzia lebbeck, was studied on cognitive behavior and anxiety in albino mice. The elevated plus maze was used for assessment of both nootropic and anxiolytic activity. The nootropic activity was evaluated by recording the effect of BF (0, 10, 25, and 50 mg/kg) on the transfer latency, whereas anxiolytic activity was assessed by studying its effect on the duration of occupancy in the closed arm. Results showed significant improvement in the retention ability of the normal and amnesic mice as compared to their respective controls. Animals treated with BF (25 mg/kg) spent more time in the open arm in a dose-dependent manner. The BF was without any significant effect on motor coordination. However, it significantly inhibited passivity and hypothermia induced by baclofen (10 mg/kg), a GABA(B) agonist. The data emanated in the present study suggests involvement of gamma-aminobutyric acid (GABA) in the nootropic and anxiolytic activity of saponins obtained from A. lebbeck.

  20. Short-term desensitization of G-protein-activated, inwardly rectifying K+ (GIRK) currents in pyramidal neurons of rat neocortex.

    Science.gov (United States)

    Sickmann, Thomas; Alzheimer, Christian

    2003-10-01

    Whole cell recordings from acutely isolated rat neocortical pyramidal cells were performed to study the kinetics and the mechanisms of short-term desensitization of G-protein-activated, inwardly rectifying K+ (GIRK) currents during prolonged application (5 min) of baclofen, adenosine, or serotonin. Most commonly, desensitization of GIRK currents was characterized by a biphasic time course with average time constants for fast and slow desensitization in the range of 8 and 120 s, respectively. The time constants were independent of the agonist used to evoke the current. The biphasic time course was preserved in perforated-patch recordings, indicating that neither component of desensitization is attributable to cell dialysis. Desensitization of GIRK currents displayed a strong heterologous component in that application of a second agonist substantially reduced the responsiveness to a test agonist. Fast desensitization, but not slow desensitization, was lost in cells loaded with GDP, suggesting that the hydrolysis cycle of G proteins might underlie the initial, rapid current decline. Hydrolysis of phosphatidylinositol biphosphate is an unlikely candidate underlying short-term desensitization, because both components of desensitization were preserved in the presence of the phospholipase C inhibitor U73122. We conclude that short-term desensitization does neither result from receptor downregulation nor from altered channel gating but might involve modifications of the G-protein-dependent pathway that serves to translate receptor activation into channel opening.

  1. Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update.

    Science.gov (United States)

    Tazir, Meriem; Hamadouche, Tarik; Nouioua, Sonia; Mathis, Stephane; Vallat, Jean-Michel

    2014-12-15

    Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment.

  2. Selectivity Enhancement in Molecularly Imprinted Polymers for Binding of Bisphenol A.

    Science.gov (United States)

    Alenazi, Noof A; Manthorpe, Jeffrey M; Lai, Edward P C

    2016-10-14

    Bisphenol A (BPA) is an estrogen-mimicking chemical that can be selectively detected in water using a chemical sensor based on molecularly imprinted polymers (MIPs). However, the utility of BPA-MIPs in sensor applications is limited by the presence of non-specific binding sites. This study explored a dual approach to eliminating these sites: optimizing the molar ratio of the template (bisphenol A) to functional monomer (methacrylic acid) to cross-linker (ethylene glycol dimethacrylate), and esterifying the carboxylic acid residues outside of specific binding sites by treatment with diazomethane. The binding selectivity of treated MIPs and non-treated MIPs for BPA and several potential interferents was compared by capillary electrophoresis with ultraviolet detection. Baclofen, diclofenac and metformin were demonstrated to be good model interferents to test all MIPs for selective binding of BPA. Treated MIPs demonstrated a significant decrease in binding of the interferents while offering high selectivity toward BPA. These results demonstrate that conventional optimization of the molar ratio, together with advanced esterification of non-specific binding sites, effectively minimizes the residual binding of interferents with MIPs to facilitate BPA sensing.

  3. Selectivity Enhancement in Molecularly Imprinted Polymers for Binding of Bisphenol A

    Science.gov (United States)

    Alenazi, Noof A.; Manthorpe, Jeffrey M.; Lai, Edward P. C.

    2016-01-01

    Bisphenol A (BPA) is an estrogen-mimicking chemical that can be selectively detected in water using a chemical sensor based on molecularly imprinted polymers (MIPs). However, the utility of BPA-MIPs in sensor applications is limited by the presence of non-specific binding sites. This study explored a dual approach to eliminating these sites: optimizing the molar ratio of the template (bisphenol A) to functional monomer (methacrylic acid) to cross-linker (ethylene glycol dimethacrylate), and esterifying the carboxylic acid residues outside of specific binding sites by treatment with diazomethane. The binding selectivity of treated MIPs and non-treated MIPs for BPA and several potential interferents was compared by capillary electrophoresis with ultraviolet detection. Baclofen, diclofenac and metformin were demonstrated to be good model interferents to test all MIPs for selective binding of BPA. Treated MIPs demonstrated a significant decrease in binding of the interferents while offering high selectivity toward BPA. These results demonstrate that conventional optimization of the molar ratio, together with advanced esterification of non-specific binding sites, effectively minimizes the residual binding of interferents with MIPs to facilitate BPA sensing. PMID:27754429

  4. Targeting the Glutamatergic System to Treat Pathological Gambling: Current Evidence and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Mauro Pettorruso

    2014-01-01

    Full Text Available Pathological gambling or gambling disorder has been defined by the DSM-5 as a behavioral addiction. To date, its pathophysiology is not completely understood and there is no FDA-approved treatment for gambling disorders. Glutamate is the principal excitatory neurotransmitter in the nervous system and it has been recently involved in the pathophysiology of addictive behaviors. In this paper, we review the current literature on a class of drugs that act as modulating glutamate system in PG. A total of 19 studies have been included, according to inclusion and exclusion criteria. Clinical trial and case series using glutamatergic drugs (N-acetylcysteine, memantine, amantadine, topiramate, acamprosate, baclofen, gabapentin, pregabalin, and modafinil will be presented to elucidate the effectiveness on gambling behaviors and on the related clinical dimensions (craving, withdrawal, and cognitive symptoms in PG patients. The results have been discussed to gain more insight in the pathophysiology and treatment of PG. In conclusion, manipulation of glutamatergic neurotransmission appears to be promising in developing improved therapeutic agents for the treatment of gambling disorders. Further studies are required. Finally, we propose future directions and challenges in this research area.

  5. Distonias: aspectos clínicos e terapêuticos em 64 pacientes Dystonias: clinical and therapeutic features in 64 patients

    Directory of Open Access Journals (Sweden)

    James Pitágoras de Mattos

    1996-03-01

    Full Text Available Os Autores apresentam a experiência em 64 pacientes, com as várias formas clínicas de apresentação de distonias, acompanhados no Setor de Doenças Extrapiramidais do Serviço de Neurologia do Hospital Universitário Clementino Fraga Filho da UFRJ, assim como, revisam a literatura, cotejando os resultados. O acompanhamento desses pacientes durante 5 anos e 6 meses resultou nas seguintes observações: 33 do sexo masculino e 31 do feminino; 48 brancos, 10 pardos e 6 negros; a média do tempo de doença foi 9 anos e 8 meses. Quanto à distribuição do movimento anormal, 30 (46,9% eram focais; 17 (26,6%, segmentares; 13 (20,3%, generalizadas; 3 (4,7%, hemidistonias; 1 (1,5%, multifocal. Quanto à idade de início, em 11 (17,2% se apresentou antes dos 12 anos; em 6 (9,4%, entre 13 e 20 anos; e em 47 (73,4%, após os 20 anos. Correspondiam à origem idiopática esporádica, 39 (60,9%; idiopática familiar, 6 (9,4%; sintomática, 19 (29,7%. No que se refere à abordagem terapêutica destes pacientes, destacamos o emprego de anticolinérgicos, de agonistas e antagonistas dopaminérgicos e do baclofen isolado ou associado aos anticolinérgicos para as formas generalizadas. Para as distonias focais, os Autores concluem ser a toxina botulínica do tipo A o agente terapêutico mais eficaz aconselhado atualmente.The experience with 64 patients with dystonia seen at the Extrapyramidal Diseases Sector of the Neurology Department of the Hospital Universitário Clementino Fraga Filho of the UFRJ is presented as well as the pertinent review of the literature. The five-and-a-half-year of follow-up showed that 33 were male and 31 female; 48 were white, 10 mulatto and 6 negro; the mean time of disease was 9 years and 8 months. According to the distribution of the movement disorder, 30 (46.9% were focal, 17 (26.6% segmental, 13 (20.3% generalized, 3 (4.7% hemidystonia and 1 (1.5% multifocal. In 11 (17.2% the age of onset was before 12 years old, in 6 (9

  6. Formulación de mezclas intratecales para el tratamiento del dolor Compounding of drug admixtures for intrathecal treatment of pain

    Directory of Open Access Journals (Sweden)

    M. P. Ortega-García

    2012-08-01

    intrathecal analgesia are recommended in international consensus, but there are few studies about their stability and safety. The objectives of this review are to evaluate specific considerations for compounded formulations for intrathecal pumps and to review stability studies of drug combinations recommended. Compounding formulations for intrathecal pumps has specific recommendations: avoiding preservatives, antioxidants, and solubility enhancers, using buffers that are compatible with the delivery system, using a pH that is physiologically appropriate and is consistent with the delivery system, normally between 4 and 8, using solutions isotonic with normal CSF, preparing the solution in a manner that does not alter the solubility of the constituents, verifying the chemical and physical stability of the preparation under relevant conditions in accordance with literature and verifying the sterility of the preparation in accordance with the United States Pharmacopeia (Chapter 797 and American Society of Health-System Pharmacist publications. But pharmacist, moreover compounding, play an important role in maintaining quality assurance of intrathecal drug use, validating prescriptions and using standard procedures for ordering and compounding medications, checking dose calculations and monitoring of patients outcomes. Drug combinations for intrathecal analgesia with stability studies are: morphine and ziconotide, morphine and clonidine, ziconotide and bupivacaine, morphine, bupivacaine and clonidine, morphine, ziconotide and clonidine, baclofen and clonidine, ziconotide and baclofen, ziconotide and clonidine, ziconotide and fentanyl. Except for ziconotide combinations, concentration of drugs remains over 90% during 90 days. But ziconotide is very unstable and admixtures with other drugs can accelerate the rate of ziconotide degradation.

  7. Effect of Early Acupuncture at Huatuo Jiajipoints on Striatalβ-endorphin and Dynorphin Levels in MCAO Rats%早期针刺夹脊穴对 MCAO 大鼠脑纹状体β-内啡肽和强啡肽水平的影响

    Institute of Scientific and Technical Information of China (English)

    王春琛; 王麟鹏

    2016-01-01

    Objective To investigate the effect of early acupuncture at Huatuo jiaji points on striatalβ-endorphin and dynorphin levels in rats with post-stroke limb spasm.Methods Seventy SD rats were randomized into group A (normal) of 9 rats and group B (sham operation) of 10 rats. After a model of post-stroke limb spasm was made in the remaining rats, they were randomized into groups C (model), D (acupuncture at Huatuo jiaji points) and E (baclofen). Group D received acupuncture at Huatuo jiaji points and group E, an oral gavage of baclofen tablets. After seven days of treatment, striatalβ-endorphin and dynorphin levels were neasured by radioimmunoassay.Resultsβ-endorphin levels increased significantly in groups C, D and E compared with groups A and B (P0.05). Dynorphin levels increased significantly in groups C, D and E compared with groups A and B (P0.05).Conclusions Acupuncture at Huatuo jiaji points can increase striatalβ-endorphin levels but not change striatal dynorphin levels, which conforms to the relationship between enkephalin and spasm, and improve the animal’s spasticity.%目的:观察早期针刺夹脊穴对卒中后肢体痉挛大鼠脑纹状体β-内啡肽和强啡肽水平的影响。方法将70只SD大鼠随机分为A组(正常组)9只和B组(假手术组)10只,剩余大鼠制备卒中后肢体痉挛大鼠模型后随机分为C组(模型组)、D组(针刺夹脊穴组)和E组(巴氯芬组)。D组采用针刺夹脊穴治疗,E组采用巴氯芬片灌胃治疗。治疗7 d后,采用放射免疫方法检测各组动物脑纹状体β-内啡肽和强啡肽水平。结果与A组和B组比较,C组、D组和E组β-内啡肽水平均显著升高(P<0.01);与C组比较,D组和E组β-内啡肽水平均显著升高(P<0.01,P<0.05);D组β-内啡肽水平与E组比较,差异无统计学意义(P>0.05)。与A组和B组比较,C组、D组和E组内强啡肽水平均均显著升高(P<0.05,P<0.01);D组内强啡肽水平和E组比

  8. INHIBITORY EFFECT OF GABA ON FIRING ACTIVITY OF ROSTRAL VENTROLATERAL MEDULLARY NEURONS OF RAT IN VITRO%γ-氨基丁酸对离体大鼠延髓头端腹外侧区神经元单位放电的抑制作用

    Institute of Scientific and Technical Information of China (English)

    储祥平; 李鹏; 徐宁善

    1998-01-01

    Extracellular single-unit discharges were obtained from 106 spontaneously active neurons in the region of the rostral ventrolateral medulla (RVLM) by glass microelectrode from 73 brain slices of Sprague-Dawley rats. Exogenous γ-aminobutyric acid (GABA, 0.1 ~ 3.0 mmol/L) inhibited the electrical activity of 84 out of 106 RVLM neurons dose-dependently. The inhibitory effect of GABA could be blocked by GABAA with BMI or PTX alone, the firing rates of most of the RVLM neurons were significantly increased. In 41 neurons responding to GABA, baclofen (0.1 ~ 3.0 μmol/L), a GABAB receptor selective agonist, inhibited the discharges of 33 of the neurons dose-dependently. GABAB receptor antagonist CGP35348 ( n = 13) blocked the inhibition due to baclofen ( n = 21). After perfused with CGP35348 alone, the firing rates of most of the RVLM neurons were significantly increased. Taken together, the inhibition of GABA on RVLM neurons is mediated through either GABAA or GABAB receptors and some intrinsic GABA neurons exert tonic inhibition activity.%在73张脑片上观察了γ-氨基丁酸(GABA)对106个延髓头端腹外侧区(RVLM)神经元单位放电的影响.外源性的GABA(0.1~3.0 mmol/L)抑制了106神经元中的84个神经元的电活动,这些抑制效应呈剂量-反应关系.GABA的抑制效应大部分可被GABAA受体选择性拮抗剂荷苞牡丹碱甲基碘化物(BMI)和Cl-通道阻断剂印防己毒素(PTX)所阻断,而单独灌流BMI和PTX对RVLM神经元主要起兴奋作用.在41个对GABA有抑制效应的RVLM神经元上,GABAB受体选择性激动剂苯氯丁氨酸(0.1~3.0 μmoL/L)抑制了其中33个神经元的单位放电,也呈剂量-反应关系.GABAB受体选择性拮抗剂CGP35348(n=13)可阻断苯氯丁氨酸的抑制效应(n=21),而单独灌流CGP35348对RVLM神经元主要起兴奋作用.上述结果提示:GABA对RVLM神经元的抑制效应,不仅可以通过GABAA受体,而且可以通过GABAB受体起作用;内源性的GABA参与了紧张性的抑制作用.

  9. Clinical characteriscs of stiff-person syndrome%僵人综合征4例分析及文献回顾

    Institute of Scientific and Technical Information of China (English)

    冯兵; 李洵桦; 龙健中; 杨培全; 李欣明

    2011-01-01

    Objective The clinical features of stiff-person syndrome (SPS) were described in order to improve the diagnosis.Methods The clinical manifestations, typical electromyogram (EMG) findings and the therapeutic effects of the 4 cases were summarize.Results In the 4 cases,3 were males and 1 was female.Their ages were between 29 to 51.One case had the onset of the disease after catching a cold, other cases had no inducement.No special past history or family history was found.2 cases had subacute onset and 2 had chronic onset of the disease.The durations of the disease were between 1 to 13 months.The chief clinical manifestations were paroxysmal or persistant stiffness and pain in the muscles of proximal limbs and trunk, and then dyskinesia of the relevant sites.Persistant MUAPs were recorded in EMG at rest,but disappeared after valium injection.After treated by benzodiazepines and baclofen,2 cases were recovered, and 2 cases had no progression of the symptoms.Conclusions Stiff-person syndrome is a rare muscle disease which is easy to mistake in diagnosis.Benzodiazepines and baclofen could have good curative effect.%目的 总结僵人综合征的临床特点,提高对该病的认识和诊断水平.方法 分析4例病例,总结其临床表现、典型的肌电图表现及治疗效果.结果 4例患者3名男性,1名女性,年龄29岁~51岁,1例为受凉约2w后出现症状,3例无明显诱发因素.4例既往均无特殊疾病史,亦无家族同类病史.2例为亚急性起病,2例为慢性起病,病程分别为1~13个月.主要表现为躯干、四肢近端肌肉出现阵发或持续性僵硬和疼痛,从而引起相应部位的运动障碍.4例均行常规肌电图检查,显示在放松状态下时有持续运动单位电位,应用安定后消失.经苯二氮草类、巴氯芬治疗后2例可痊愈,另2例亦无反复发作及恶化.结论 僵人综合征是一种罕见的肌肉疾病,易误诊,苯二氮草类、巴氯芬治疗可获良好效果.

  10. Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design

    Directory of Open Access Journals (Sweden)

    Keppel Hesselink JM

    2017-03-01

    , cream, gel, dose-finding, formulation, ketamine, amitriptyline, baclofen, enrichment

  11. Cross-talk between membrane-initiated and nuclear-initiated oestrogen signaling in the hypothalamus

    Science.gov (United States)

    Roepke, Troy A.; Qiu, Jian; Bosch, Martha A.; Rønnekleiv, Oline K.; Kelly, Martin J.

    2009-01-01

    It is increasingly evident that 17β-oestradiol (E2) via a distinct membrane oestrogen receptor (Gq-mER) can rapidly activate kinase pathways to have multiple downstream actions in CNS neurons. We have found that E2 can rapidly reduce the potency of the GABAB receptor agonist baclofen and mu-opioid receptor agonist DAMGO to activate G protein-coupled, inwardly rectifying K+ (GIRK) channels in hypothalamic neurons, thereby increasing the excitability (firing activity) of POMC and dopamine neurons. These effects are mimicked by the membrane impermeant E2-BSA and a new ligand (STX) that is selective for the Gq-mER that does not bind to ERα or ERβ. Both E2 and STX are fully efficacious in attenuating the GABAB response in ERα, ERβ and GPR 30 knockout mice in an ICI 182,780 reversible manner. These findings are further proof that E2 signals through a unique plasma membrane ER. We have characterised the coupling of this Gq-mER to a Gq-mediated activation of phospholipase C leading to the up-regulation of protein kinase Cδ and protein kinase A activity in these neurons, which ultimately alters gene transcription. Finally as proof of principle, we have found that STX, like E2, reduces food intake and body weight gain in ovariectomised females. STX, presumably via the Gq-mER, also regulates gene expression of a number of relevant targets including cation channels and signalling molecules that are critical for regulating (as a prime example) POMC neuronal excitability. Therefore, E2 can activate multiple receptor-mediated pathways to modulate excitability and gene transcription in CNS neurons that are critical for controlling homeostasis and motivated behaviors. PMID:19187465

  12. Modulation of sensitivity to alcohol by cortical and thalamic brain regions.

    Science.gov (United States)

    Jaramillo, Anel A; Randall, Patrick A; Frisbee, Suzanne; Besheer, Joyce

    2016-10-01

    The nucleus accumbens core (AcbC) is a key brain region known to regulate the discriminative stimulus/interoceptive effects of alcohol. As such, the goal of the present work was to identify AcbC projection regions that may also modulate sensitivity to alcohol. Accordingly, AcbC afferent projections were identified in behaviorally naïve rats using a retrograde tracer which led to the focus on the medial prefrontal cortex (mPFC), insular cortex (IC) and rhomboid thalamic nucleus (Rh). Next, to examine the possible role of these brain regions in modulating sensitivity to alcohol, neuronal response to alcohol in rats trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water was examined using a two-lever drug discrimination task. As such, rats were administered water or alcohol (1 g/kg, IG) and brain tissue was processed for c-Fos immunoreactivity (IR), a marker of neuronal activity. Alcohol decreased c-Fos IR in the mPFC, IC, Rh and AcbC. Lastly, site-specific pharmacological inactivation with muscimol + baclofen (GABAA agonist + GABAB agonist) was used to determine the functional role of the mPFC, IC and Rh in modulating the interoceptive effects of alcohol in rats trained to discriminate alcohol (1 g/kg, IG) vs. water. mPFC inactivation resulted in full substitution for the alcohol training dose, and IC and Rh inactivation produced partial alcohol-like effects, demonstrating the importance of these regions, with known projections to the AcbC, in modulating sensitivity to alcohol. Together, these data demonstrate a site of action of alcohol and the recruitment of cortical/thalamic regions in modulating sensitivity to the interoceptive effects of alcohol.

  13. Caudal Nucleus Accumbens Core Is Critical in the Regulation of Cue-Elicited Approach-Avoidance Decisions

    Science.gov (United States)

    Hamel, Laurie; Thangarasa, Tharshika; Samadi, Osai

    2017-01-01

    The nucleus accumbens (NAc) is thought to be a site of integration of positively and negatively valenced information and action selection. Functional differentiation in valence processing has previously been found along the rostrocaudal axis of the shell region of the NAc in assessments of unconditioned motivation. Given that the core region of the NAc has been implicated in the elicitation of motivated behavior in response to conditioned cues, we sought to assess the role of caudal, intermediate, and rostral sites within this subregion in cue-elicited approach-avoidance decisions. Rats were trained to associate visuo-tactile cues with appetitive, aversive, and neutral outcomes. Following the successful acquisition of the cue-outcome associations, rats received microinfusions of GABAA and GABAB receptor agonists (muscimol/baclofen) or saline into the caudal, intermediate, or rostral NAc core and were then exposed to a superimposition of appetitively and aversively valenced cues versus neutral cues in a “conflict test,” as well as to the appetitive versus neutral cues, and aversive cues versus neutral cues, in separate conditioned preference/avoidance tests. Disruption of activity in the intermediate to caudal parts of the NAc core resulted in a robust avoidance bias in response to motivationally conflicting cues, as well as a potentiated avoidance of aversive cues as compared with control animals, coupled with an attenuated conditioned preference for the appetitive cue. These results suggest that the caudal NAc core may have the capacity to exert bidirectional control over appetitively and aversively motivated responses to valence signals. PMID:28275709

  14. Effects of imipramine or GABA(B) receptor ligands on the immobility, swimming and climbing in the forced swim test in rats following discontinuation of cocaine self-administration.

    Science.gov (United States)

    Frankowska, Małgorzata; Gołda, Anna; Wydra, Karolina; Gruca, Piotr; Papp, Mariusz; Filip, Małgorzata

    2010-02-10

    We tested if discontinuation of cocaine self-administration can lead to the development of depressive-like symptoms in the forced swim test expressed as changes in immobility, swimming and climbing behaviors in rats. A "yoked" procedure in which rats were run simultaneously in groups of three, with two rats received the passive injection of cocaine or saline, was employed. Later, we examined whether acute treatment with the classical antidepressant imipramine or GABA(B) receptor ligands could alter the increases in immobility recorded after discontinuation of self-administered cocaine. We found a significant increase (44%) in the immobility time 3 days following discontinuation of cocaine (0.5mg/kg/infusion/2h daily) self-administration for 14 days; such enhancement resembled that observed in rats following the chronic mild stress. Acute administration with imipramine (15 or 30 mg/kg), the GABA(B) receptor agonists baclofen (0.125 mg/kg) and SKF 97541 (0.005 mg/kg), the positive allosteric modulator CGP 7930 (0.3mg/kg) or the antagonist SCH 50911 (0.3mg/kg) counteracted the cocaine discontinuation-induced enhancement in the immobility time. The enhanced immobility time in rats that self-administered cocaine (but not given cocaine passively) may reflect the motivated or cognitive processes of reinforced responding of cocaine and could be a potential driver of the addiction process per se. Moreover, either blockade or stimulation of GABA(B) receptors by their ligands in very low doses attenuated the enhanced immobility time in rats after discontinuation of cocaine self-administration and these findings extend preclinical studies demonstrating the potential involvement of GABA(B) receptor ligands to reduce cocaine craving.

  15. γ-Hydroxybutyrate and the GABAergic footprint: a metabolomic approach to unpicking the actions of GHB.

    Science.gov (United States)

    Nasrallah, Fatima A; Maher, Anthony D; Hanrahan, Jane R; Balcar, Vladimir J; Rae, Caroline D

    2010-10-01

    Gamma-hydroxybutyrate is found both naturally in the brain and self-administered as a drug of abuse. It has been reported to act at endogenous γ-hydroxybutyrate (GHB) receptors and GABA(B) receptors [GABA(B)R], and may also be metabolized to GABA. Here, the metabolic fingerprints of a range of concentrations of GHB were measured in brain cortical tissue slices and compared with those of ligands active at GHB and GABA-R using principal components analysis (PCA) to identify sites of GHB activity. Low concentrations of GHB (1.0 μM) produced fingerprints similar to those of ligands active at GHB receptors and α4-containing GABA(A)R. A total of 10 μM GHB clustered proximate to mainstream GABAergic synapse ligands, such as 1.0 μM baclofen, a GABA(B)R agonist. Higher concentrations of GHB (30 μM) clustered with GABA(C)R agonists and the metabolic responses induced by blockade of the GABA transporter-1 (GAT1). The metabolic responses induced by 60 and 100 μM GHB were mimicked by simultaneous blockade of GAT1 and GAT3, addition of low concentrations of GABA(C)R antagonists, or increasing cytoplasmic GABA concentrations by incubation with the GABA transaminase inhibitor vigabatrin. These data suggest that at concentrations > 30 μM, GHB may be active via metabolism to GABA, which is then acting upon an unidentified GABAergic master switch receptor (possibly a high-affinity extrasynaptic receptor), or GHB may itself be acting directly on an extrasynaptic GABA-R, capable of turning off large numbers of cells. These results offer an explanation for the steep dose-response curve of GHB seen in vivo, and suggest potential target receptors for further investigation.

  16. Effects of pharmacological manipulation of GABAergic neurotransmission in a new mutant hamster model of paroxysmal dystonia.

    Science.gov (United States)

    Fredow, G; Löscher, W

    1991-01-10

    Attacks of sustained dystonic postures of limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage) in an inbred line of Syrian hamsters. The severity of the dystonic syndrome in these mutant hamsters (gene symbol dtsz) is age-dependent, with a peak at about 30-40 days of age. A scoring system for grading type and severity of the dystonic attacks can be used to study the activity of drugs against dystonic movements with individual pre- and post-drug vehicle trials as control. In the present experiments, the effects of drugs which alter GABAergic functions in the brain were studied in dystonic hamsters. Anticonvulsants, i.e. valproate, diazepam and phenobarbital, which augment GABAergic neurotransmission, decreased the severity of dystonic attacks in the mutant hamsters, while administration of subconvulsive doses of pentylenetetrazol or the inverse benzodiazepine receptor agonist FG 7142 increased the severity of the syndrome. Anticonvulsants, i.e. phenytoin and carbamazepine, which are not thought to act via effects on GABAergic neurotransmission, exerted no antidystonic effects, but even worsened the attack in several animals. In contrast, the GABA-elevating drug, aminooxyacetic acid, produced a marked antidystonic effect in the hamsters. Similarly, the GABAB receptor agonist, baclofen, significant decreased the severity of the dystonic attack. The data indicate that dystonic movements in dtsz mutant hamsters can be attenuated by drugs which facilitate GABAergic functions, but worsened by drugs which impair GABAergic neurotransmission. These data thus seem to suggest that the dystonic syndrome in dtsz mutant hamsters is under GABAergic influence. The data show furthermore that dystonic hamsters are a suitable model to detect antidystonic effects of drugs.

  17. Coadministration of intrathecal strychnine and bicuculline effects synergistic allodynia in the rat: an isobolographic analysis.

    Science.gov (United States)

    Loomis, C W; Khandwala, H; Osmond, G; Hefferan, M P

    2001-03-01

    Tactile allodynia can be modeled in experimental animals by acutely blocking spinal glycine or GABA(A) receptors with intrathecal (i.t.) strychnine (STR) or bicuculline (BIC), respectively. To test the hypothesis that glycine and GABA effect cooperative (supra-additive) inhibition of touch-evoked responses in the spinal cord, male Sprague-Dawley rats, fitted with chronic i.t. catheters, were used. Following i.t. STR, BIC, or STR + BIC, hair deflection evoked cardiovascular (increased blood pressure and heart rate), motor (scratching, kicking and rippling of the affected dermatomes), and cortical encephalographic responses. Hair deflection was without effect in i.t. saline-treated rats. Isobolographic analysis of STR (ED(50) = 25.1-36.9 microg), BIC (ED(50) = 0.5-0.6 microg), and BIC:STR combination (ED(50) = 0.026-0.034:2.6-3.4 microg) dose-response curves confirmed a supra-additive interaction between BIC and STR in this model. BIC-allodynia was reproduced by i.t. picrotoxin. Pretreatment with i.t. scopolamine, or i.t. muscarine had no effect. STR-allodynia was dose dependently inhibited by i.t. muscimol but not baclofen. The results of this study indicate that 1) glycine and GABA effect cooperative inhibition of low-threshold mechanical input in the spinal cord of the rat; and 2) BIC-allodynia arises from the blockade of GABA(A) receptors and is unrelated to any secondary anticholinesterase activity. The allodynic state induced by the blockade of glycine or GABA receptors is clearly exacerbated by the removal of both inhibitory systems. Their combined loss after neural injury may explain the exaggerated sensitivity to and subsequent miscoding of tactile information as pain.

  18. Release of a single neurotransmitter from an identified interneuron coherently affects motor output on multiple time scales.

    Science.gov (United States)

    Dacks, Andrew M; Weiss, Klaudiusz R

    2013-05-01

    Neurotransmitters can have diverse effects that occur over multiple time scales often making the consequences of neurotransmission difficult to predict. To explore the consequences of this diversity, we used the buccal ganglion of Aplysia to examine the effects of GABA release by a single interneuron, B40, on the intrinsic properties and motor output of the radula closure neuron B8. B40 induces a picrotoxin-sensitive fast IPSP lasting milliseconds in B8 and a slow EPSP lasting seconds. We found that the excitatory effects of this slow EPSP are also mediated by GABA. Together, these two GABAergic actions structure B8 firing in a pattern characteristic of ingestive programs. Furthermore, we found that repeated B40 stimulation induces a persistent increase in B8 excitability that was occluded in the presence of the GABA B receptor agonist baclofen, suggesting that GABA affects B8 excitability over multiple time scales. The phasing of B8 activity during the feeding motor programs determines the nature of the behavior elicited during that motor program. The persistent increase in B8 excitability induced by B40 biased the activity of B8 during feeding motor programs causing the motor programs to become more ingestive in nature. Thus, a single transmitter released from a single interneuron can have consequences for motor output that are expressed over multiple time scales. Importantly, despite the differences in their signs and temporal characteristics, the three actions of B40 are coherent in that they promote B8 firing patterns that are characteristic of ingestive motor outputs.

  19. At immature mossy fibers-CA3 connections, activation of presynaptic GABAB receptors by endogenously released GABA contributes to synapses silencing

    Directory of Open Access Journals (Sweden)

    Victoria F Safiulina

    2009-02-01

    Full Text Available Early in postnatal life correlated GABAergic activity in the hippocampus is thought to play a crucial role in synaptogenesis and in the development of adult neuronal networks. Unlike adulthood, at this developmental stage, mossy fibers (MF which are the axons of granule cells, release GABA into CA3 principal cells and interneurons. Here, we tested the hypothesis that at MF-CA3 connections, tonic activation of GABAB autoreceptors by GABA is responsible for the low probability of release and synapse silencing. Blocking GABAB receptors with CGP55845 enhanced the probability of GABA release and switched on silent synapses while the opposite was observed with baclofen. Both these effects were presynaptic and were associated with changes in paired-pulse ratio and coefficient of variation. In addition, enhancing the extracellular GABA concentration by repetitive stimulation of MF or by blocking the GABA transporter GAT-1, switched off active synapses, an effect that was prevented by CGP55845. In the presence of CGP55845, stimulation of MF induced synaptic potentiation. The shift of EGABA from the depolarizing to the hyperpolarizing direction with bumetanide, a blocker of the cation-chloride co-transporter NKCC1, prevented synaptic potentiation and caused synaptic depression, suggesting that the depolarizing action of GABA observed in the presence of CGP55845 is responsible for the potentiating effect. It is proposed that, activation of GABAB receptors by spillover of GABA from MF terminals reduces the probability of release and contributes to synapses silencing. This would act as a filter to prevent excessive activation of the auto-associative CA3 network and the emergence of seizures.

  20. Unilateral inactivation of the basolateral amygdala attenuates context-induced renewal of Pavlovian-conditioned alcohol-seeking.

    Science.gov (United States)

    Chaudhri, N; Woods, C A; Sahuque, L L; Gill, T M; Janak, P H

    2013-09-01

    Environmental contexts associated with drug use promote craving in humans and drug-seeking in animals. We hypothesized that the basolateral amygdala (BLA) itself as well as serial connectivity between the BLA and nucleus accumbens core (NAC core) were required for context-induced renewal of Pavlovian-conditioned alcohol-seeking. Male Long-Evans rats were trained to discriminate between two conditioned stimuli (CS): a CS+ that was paired with ethanol (EtOH, 20%, v/v) delivery into a fluid port (0.2 mL/CS+, 3.2 mL per session) and a CS- that was not. Entries into the port during each CS were measured. Next, rats received extinction in a different context where both cues were presented without EtOH. At test, responding to the CS+ and CS- without EtOH was evaluated in the prior training context. Control subjects showed a selective increase in CS+ responding relative to extinction, indicative of renewal. This effect was blocked by pre-test, bilateral inactivation of the BLA using a solution of GABA receptor agonists (0.1 mm muscimol and 1.0 mm baclofen; M/B; 0.3 μL per side). Renewal was also attenuated following unilateral injections of M/B into the BLA, combined with either M/B, the dopamine D1 receptor antagonist SCH 23390 (0.6 μg per side) or saline infusion in the contralateral NAC core. Hence, unilateral BLA inactivation was sufficient to disrupt renewal, highlighting a critical role for functional activity in the BLA in enabling the reinstatement of alcohol-seeking driven by an alcohol context.

  1. Exposure to novelty and forced swimming evoke stressor-dependent changes in extracellular GABA in the rat hippocampus.

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    de Groote, L; Linthorst, A C E

    2007-09-07

    In the hippocampus, a brain structure critically important in the stress response, GABA controls neuronal activity not only via synaptic inhibition, but also via tonic inhibition through stimulation of extrasynaptic GABA receptors. The extracellular level of GABA may represent a major determinant for tonic inhibition and, therefore, it is surprising that its responsiveness to stress has hardly been investigated. To clarify whether hippocampal extracellular GABA levels change in response to acute stress, we conducted an in vivo microdialysis study in rats. We found that dialysate GABA levels respond to various neuropharmacological manipulations such as reuptake inhibition, elevated concentrations of K(+), tetrodotoxin and baclofen, indicating that a large proportion of hippocampal extracellular GABA depends on neuronal release and that GABA re-uptake plays a role in determining the extracellular levels of this neurotransmitter. Next, rats were exposed to a novel cage or to forced swimming in 25 degrees C water. Interestingly, these two stressors resulted in opposite effects. Novelty caused a fast increase in GABA (120% of baseline), whereas forced swimming resulted in a profound decrease (70% of baseline). To discriminate between the psychological and physical aspects (i.e. the effects on body temperature) of forced swimming, another group of animals was forced to swim at 35 degrees C. This stressor, like novelty, caused an increase in hippocampal GABA, suggesting a stimulatory effect of psychological stress. The effects of novelty could not be blocked by the corticotropin-releasing factor receptor antagonist D-Phe-CRF(12-41). These results are the first to demonstrate stressor-dependent changes in hippocampal extracellular GABA; an observation which may be of particular significance for GABAergic tonic inhibition of hippocampal neurons.

  2. GABA systems, benzodiazepines, and substance dependence.

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    Malcolm, Robert J

    2003-01-01

    Alterations in the gamma-aminobutyric acid (GABA) receptor complex and GABA neurotransmission influence the reinforcing and intoxicating effects of alcohol and benzodiazepines. Chronic modulation of the GABA(A)-benzodiazepine receptor complex plays a major role in central nervous system dysregulation during alcohol abstinence. Withdrawal symptoms stem in part from a decreased GABAergic inhibitory function and an increase in glutamatergic excitatory function. GABA(A) receptors play a role in both reward and withdrawal phenomena from alcohol and sedative-hypnotics. Although less well understood, GABA(B) receptor complexes appear to play a role in inhibition of motivation and diminish relapse potential to reinforcing drugs. Evidence suggests that long-term alcohol use and concomitant serial withdrawals permanently alter GABAergic function, down-regulate benzodiazepine binding sites, and in preclinical models lead to cell death. Benzodiazepines have substantial drawbacks in the treatment of substance use-related disorders that include interactions with alcohol, rebound effects, alcohol priming, and the risk of supplanting alcohol dependency with addiction to both alcohol and benzodiazepines. Polysubstance-dependent individuals frequently self-medicate with benzodiazepines. Selective GABA agents with novel mechanisms of action have anxiolytic, anticonvulsant, and reward inhibition profiles that have potential in treating substance use and withdrawal and enhancing relapse prevention with less liability than benzodiazepines. The GABA(B) receptor agonist baclofen has promise in relapse prevention in a number of substance dependence disorders. The GABA(A) and GABA(B) pump reuptake inhibitor tiagabine has potential for managing alcohol and sedative-hypnotic withdrawal and also possibly a role in relapse prevention.

  3. AMP kinase regulates ligand-gated K-ATP channels in substantia nigra dopamine neurons.

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    Shen, Ke-Zhong; Wu, Yan-Na; Munhall, Adam C; Johnson, Steven W

    2016-08-25

    AMP-activated protein kinase (AMPK) is a master enzyme that regulates ATP-sensitive K(+) (K-ATP) channels in pancreatic beta-cells and cardiac myocytes. We used patch pipettes to record currents and potentials to investigate effects of AMPK on K-ATP currents in substantia nigra compacta (SNC) dopamine neurons in slices of rat midbrain. When slices were superfused repeatedly with the K-ATP channel opener diazoxide, we were surprised to find that diazoxide currents gradually increased in magnitude, reaching 300% of the control value 60min after starting whole-cell recording. However, diazoxide current increased significantly more, to 472% of control, when recorded in the presence of the AMPK activator A769662. Moreover, superfusing the slice with the AMPK blocking agent dorsomorphin significantly reduced diazoxide current to 38% of control. Control experiments showed that outward currents evoked by the K-ATP channel opener NN-414 also increased over time, but not currents evoked by the GABAB agonist baclofen. Delaying the application of diazoxide after starting whole-cell recording correlated with augmentation of current. Loose-patch recording showed that diazoxide produced a 34% slowing of spontaneous firing rate that did not intensify with repeated applications of diazoxide. However, superfusion with A769662 significantly augmented the inhibitory effect of diazoxide on firing rate. We conclude that K-ATP channel function is augmented by AMPK, which is activated during the process of making whole-cell recordings. Our results suggest that AMPK and K-ATP interactions may play an important role in regulating dopamine neuronal excitability.

  4. At immature mossy fibers-CA3 connections, activation of presynaptic GABA(B) receptors by endogenously released GABA contributes to synapses silencing.

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    Safiulina, Victoria F; Cherubini, Enrico

    2009-01-01

    Early in postnatal life correlated GABAergic activity in the hippocampus is thought to play a crucial role in synaptogenesis and in the development of adult neuronal networks. Unlike adulthood, at this developmental stage, mossy fibers (MF) which are the axons of granule cells, release GABA into CA3 principal cells and interneurons. Here, we tested the hypothesis that at MF-CA3 connections, tonic activation of GABA(B) autoreceptors by GABA is responsible for the low probability of release and synapse silencing. Blocking GABA(B) receptors with CGP55845 enhanced the probability of GABA release and switched on silent synapses while the opposite was observed with baclofen. Both these effects were presynaptic and were associated with changes in paired-pulse ratio and coefficient of variation. In addition, enhancing the extracellular GABA concentration by repetitive stimulation of MF or by blocking the GABA transporter GAT-1, switched off active synapses, an effect that was prevented by CGP55845. In the presence of CGP55845, stimulation of MF-induced synaptic potentiation. The shift of E(GABA) from the depolarizing to the hyperpolarizing direction with bumetanide, a blocker of the cation-chloride co-transporter NKCC1, prevented synaptic potentiation and caused synaptic depression, suggesting that the depolarizing action of GABA observed in the presence of CGP55845 is responsible for the potentiating effect. It is proposed that, activation of GABA(B) receptors by spillover of GABA from MF terminals reduces the probability of release and contributes to synapses silencing. This would act as a filter to prevent excessive activation of the auto-associative CA3 network and the emergence of seizures.

  5. The bed nucleus of the stria terminalis regulates ethanol-seeking behavior in mice.

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    Pina, Melanie M; Young, Emily A; Ryabinin, Andrey E; Cunningham, Christopher L

    2015-12-01

    Drug-associated stimuli are considered important factors in relapse to drug use. In the absence of drug, these cues can trigger drug craving and drive subsequent drug seeking. One structure that has been implicated in this process is the bed nucleus of the stria terminalis (BNST), a chief component of the extended amygdala. Previous studies have established a role for the BNST in cue-induced cocaine seeking. However, it is unclear if the BNST underlies cue-induced seeking of other abused drugs such as ethanol. In the present set of experiments, BNST involvement in ethanol-seeking behavior was assessed in male DBA/2J mice using the conditioned place preference procedure (CPP). The BNST was inhibited during CPP expression using electrolytic lesions (Experiment 1), co-infusion of GABAA and GABAB receptor agonists muscimol and baclofen (M+B; Experiment 2), and activation of inhibitory designer receptors exclusively activated by designer drugs (hM4Di-DREADD) with clozapine-N-oxide (CNO; Experiment 3). The magnitude of ethanol CPP was reduced significantly by each of these techniques. Notably, infusion of M+B (Exp. 2) abolished CPP altogether. Follow-up studies to Exp. 3 showed that ethanol cue-induced c-Fos immunoreactivity in the BNST was reduced by hM4Di activation (Experiment 4) and in the absence of hM4Di, CNO did not affect ethanol CPP (Experiment 5). Combined, these findings demonstrate that the BNST is involved in the modulation of cue-induced ethanol-seeking behavior.

  6. Kindling-induced changes in EEG recorded during stimulation from the site of stimulation. III. Direct pharmacological manipulations of the kindled amygdala.

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    Morimoto, K; Holmes, K H; Goddard, G V

    1987-07-01

    In our previous studies, we hypothesized that activation and subsequent collapse of GABA-mediated inhibition during tetanus is an important seizure-triggering mechanism in the kindled epileptogenic focus. To examine this hypothesis, in the present study, we investigated the effects of pharmacological manipulations of the kindled amygdala with several drugs, and measured the kindled seizures as well as the EEG events during tetanus. The results obtained were: (i) The selective GABA-A agonist, muscimol (1 and 5 nM/1 microliter), suppressed kindled seizures in a dose-dependent fashion, and the 5 nM muscimol significantly prolonged EEG suppression and reduced the number of oscillations in the subsequent rhythmic synchronous discharge. Similar effects followed systemic injection of diazepam (2 mg/kg). (ii) The selective GABA-B agonist, baclofen (5 nM), had no effect on kindled seizures nor on the EEG events during tetanus. (iii) The NMDA antagonist, 2-amino-5-phosphonovaleric acid (80 nM), significantly reduced the afterdischarge duration and significantly delayed the appearance of the rhythmic synchronous discharge. However, these effects were not observed immediately, but 24 to 72 h after microinjection. (iv) The muscarinic cholinergic antagonist, atropine (40 and 80 nM), suppressed kindled seizures in a dose-dependent fashion, but the atropine caused marked synchronous discharge both in the awake resting EEG and during tetanic stimulation. We conclude that the GABA-A system, including the benzodiazepine system, is more involved in the seizure-triggering mechanism of amygdala kindling than the GABA-B system, that there is an interaction between the GABA-A and NMDA system, and that the cholinergic participation is independent of the primary seizure-triggering mechanisms.

  7. ANTI-DEPRESSANT POTENTIAL OF GHIYA

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    Kaur Satbir

    2012-04-01

    Full Text Available Lagenaria siceraria (Cucurbitaceae, popularly known as bottle gourd, lauki or ghiya, is a climbing plant, which bears hard-shelled and bottle-shaped gourds as fruits. Ghiya forms an excellent diet for people having digestive problems being rich in vitamins, iron and minerals. Since, it contains low calories, bottle gourd is an awesome foodstuff for shedding extra calories. The fruit possesses diuretic, emetic, and refrigerant properties. The ghiya (lauki juice is helpful in constipation, premature graying hair, urinary disorders and insomnia. However, there are no reports in literature pertaining to CNS actions of Lagenaria siceraria fruit. In the light of above, the present study was undertaken to test the anti-depressant potential of Lagenaria siceraria juice (LSJ. Lagenaria siceraria juice was administered at various concentrations ranging from 4%-16% v/v orally to Swiss mice (30g, once daily for 15 successive days. The anti-depressant activity was measured using Forced Swim Test (FST and Tail Suspension Test (TST. The efficacy of Lagenaria siceraria was compared to standard anti-depressant drugs viz: fluoxetine (20mg/kg, p.o, imipramine (15mg/kg, p.o and phenelzine (20 mg/kg, p.o. Lagenaria siceraria significantly reduced the immobility time of mice in both FST and TST. Prazosin, Baclofen, Sulpiride and p-CPA significantly antagonized this reduction in immobility duration. Furthermore, Lagenaria siceraria juice inhibited the monoamine oxidase (MAO enzyme and reduced significantly malondialdehyde (MDA levels. These findings reveal the anti-depressant potential of ghiya.

  8. Characterization of GABA/sub A/ receptor-mediated /sup 36/chloride uptake in rat brain synaptoneurosomes

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    Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

    1987-09-07

    ..gamma..-Aminobutyric acid (GABA) receptor-mediated /sup 36/chloride (/sup 36/Cl/sup -/) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated /sup 36/Cl/sup -/ uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-(5,4-c)pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated /sup 36/Cl/sup -/ uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated /sup 36/Cl/sup -/ uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br/sup -/>Cl/sup -/greater than or equal toNO/sub 3//sup -/>I/sup -/greater than or equal toSCN/sup -/>>C/sub 3/H/sub 5/OO/sup -/greater than or equal toClO/sub 4//sup -/>F/sup -/, consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl/sup -/ channel. 43 references, 4 figures, 3 tables.

  9. GABA increases electrical excitability in a subset of human unmyelinated peripheral axons.

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    Richard W Carr

    Full Text Available BACKGROUND: A proportion of small diameter primary sensory neurones innervating human skin are chemosensitive. They respond in a receptor dependent manner to chemical mediators of inflammation as well as naturally occurring algogens, thermogens and pruritogens. The neurotransmitter GABA is interesting in this respect because in animal models of neuropathic pain GABA pre-synaptically regulates nociceptive input to the spinal cord. However, the effect of GABA on human peripheral unmyelinated axons has not been established. METHODOLOGY/PRINCIPAL FINDINGS: Electrical stimulation was used to assess the effect of GABA on the electrical excitability of unmyelinated axons in isolated fascicles of human sural nerve. GABA (0.1-100 microM increased electrical excitability in a subset (ca. 40% of C-fibres in human sural nerve fascicles suggesting that axonal GABA sensitivity is selectively restricted to a sub-population of human unmyelinated axons. The effects of GABA were mediated by GABA(A receptors, being mimicked by bath application of the GABA(A agonist muscimol (0.1-30 microM while the GABA(B agonist baclofen (10-30 microM was without effect. Increases in excitability produced by GABA (10-30 microM were blocked by the GABA(A antagonists gabazine (10-20 microM, bicuculline (10-20 microM and picrotoxin (10-20 microM. CONCLUSIONS/SIGNIFICANCE: Functional GABA(A receptors are present on a subset of unmyelinated primary afferents in humans and their activation depolarizes these axons, an effect likely due to an elevated intra-axonal chloride concentration. GABA(A receptor modulation may therefore regulate segmental and peripheral components of nociception.

  10. Evaluation of GABA Receptors of Ventral Tegmental Area in Cardiovascular Responses in Rat

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    Minoo Rasoulpanah

    2015-07-01

    Full Text Available Background: The ventral tegmental area (VTA is well known for its role in cardiovascular control. It is demonstrated that about 20-30% of the VTA neurons are GABAergic though their role in cardiovascular control is not yet understood. This study is carried out to find the effects of GABA A and GABA B receptors on cardiovascular response of the VTA. Methods: Experiments were performed on urethane anesthetized male Wistar rats. Drugs were microinjected unilaterally into the VTA. The average changes in mean arterial pressure (MAP and heart rate (HR were compared between the case and the control groups using t test and with the pre-injection values using paired t test. Results: Microinjection of muscimol, a GABAA agonist (500, 1500 and 2500 pmol/100nl into the VTA had no significant effect on MAP and HR compared with the saline group and pre-injection values. Injection of bicuculline methiodide (BMI, 100 and 200 pmol/100 nl, a GABAA antagonist, caused a significant increase in the MAP (11.1±1.95mmHg, P<0.5 and a decrease in HR (-32.07±10.2, P<0.01. Microinjection of baclofen a GABAB receptor agonist (500 or 1000 pmole/100 nl and phaclofen a GABAB receptor antagonist (500 or 1000 pmole/100 nl had no significant effects on MAP and HR. Conclusion: For the first time it was demonstrated that GABA system of the VTA inhibits the cardiovascular system through the activation of GABAA but not the GABAB receptors.

  11. Identification of rat ventral tegmental area GABAergic neurons.

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    Elyssa B Margolis

    Full Text Available The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR activation produces reward by disinhibiting midbrain ventral tegmental area (VTA dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23±3% of VTA neurons are GAD65/67(+. In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABA(B receptor agonist baclofen (0/6 inhibited, while all confirmed dopamine neurons were inhibited (19/19. The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward.

  12. Effect of Brewer's Yeast-Induced Pyrexia on Aminophylline-Elicited Convulsions in Mice

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    Araki,Hiroaki

    2009-10-01

    Full Text Available Theophylline-associated convulsions have been observed most frequently in children with fever, but the mechanism is not fully understood. In this study, we investigated the basic mechanism of aminophylline [theophylline-2-ethylenediamine]-induced convulsions and the effects of Brewer's yeast-induced pyrexia in mice. Diazepam (5-10mg/kg, i.p., a benzodiazepine receptor agonist, significantly prolonged the onset and significantly decreased the incidence of convulsions induced by aminophylline (350mg/kg, i.p.. However, the gamma aminobutyric acid (GABAA receptor agonist muscimol (1-4mg/kg, i.p., the GABAB receptor agonist baclofen (2-4mg/kg, i.p. and the N-methyl-D-aspartic acid receptor antagonist dizocilpine (0.1-0.3mg/kg, i.p. failed to protect against the convulsions. 20% Brewer's yeast (0.02ml/g, s.c. increased body temperature by 1.03, and also significantly shortened the onset and significantly increased the incidence of convulsions induced by aminophylline. The anticonvulsant action of diazepam (2.5-10mg/kg, i.p. on the convulsions induced by aminophylline was reduced by Brewer's yeast-induced pyrexia. The proconvulsant actions of the GABAA receptor antagonists picrotoxin (3-4mg/kg, i.p. and pentylenetetrazol (40-60mg/kg, i.p. were enhanced by Brewer's yeast. These results suggest that the anticonvulsant action of diazepam against aminophylline is reduced by Brewer's yeast-induced pyrexia, and that GABAA receptors are involved in the aggravation of the convulsions by Brewer's yeast in mice.

  13. The Association between GABA-Modulators and Clostridium difficile Infection – A Matched Retrospective Case-Control Study

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    Ström, Jonathan; Tham, Johan; Månsson, Fredrik; Ahl, Jonas; Savidge, Tor C.; Dann, Sara M.

    2017-01-01

    Objective Recently, metabolomics studies have suggested that the neurotransmitter γ-amino butyric acid (GABA) may modulate C. difficile infection (CDI) pathogenesis. In the present study, we investigated the association between GABA-modulating pharmaceuticals and CDI development. Methods In July-December 2013, we performed a matched, retrospective case-control study in Skåne county, Sweden, to assess the association between the use of GABA-modulators (defined as regular use of at least one of the following: zolpidem, zopiclone, benzodiazepines, gabapentin, pregabalin or baclofen) and CDI. Multivariate regression models, adjusted for known risk factors for CDI, were fitted to assess the associations and a propensity score-adjusted analysis was performed. Results The study included 292 cases and 292 matched controls. In a multivariate regression model only recent antibiotic use (clindamycin, cephalosporins and fluoroquinolones) and nursing home residency was significantly associated with CDI. The regular use of any GABA-modulator was not associated with CDI (OR = 1.07, 95%CI 0.69–1.66, p = 0.76). The association between regular use of the selective GABA-agonist zolpidem and CDI trended towards significance (OR = 2.31, 95%CI 0.91–5.86, p = 0.078). These associations remained when only cases treated with antibiotics were included. Corresponding findings for zolpidem was observed in a propensity-score adjusted analysis (OR = 2.52, 95% CI 0.91–6.97, p = 0.075). Severe initial CDI was significantly associated with CDI recurrence (OR = 3.77, 95% CU 1.20–11.86, p = 0.023). Conclusion This study did not identify a general association between GABA-modulators and CDI. A trend towards a significant association between zolpidem and CDI was observed, an association that should be re-assessed in a study appropriately powered for this particular hypothesis. PMID:28060888

  14. Transient inactivation of the medial prefrontal cortex affects both anxiety and decision-making in male Wistar rats

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    Leonie ede Visser

    2011-09-01

    Full Text Available In both humans and rats high levels of anxiety impair decision-making in the Iowa Gambling Task (IGT in male subjects. Expression of the immediate early gene c-fos as marker of neural activity in rat studies indicated a role of the medial prefrontal cortex (prelimbic and infralimbic region; mPFC in mediating the relationship between anxiety and decision-making. To delineate this relationship further and assess the underlying neurobiology in more detail, we inactivated in the present study the mPFC in male rats using a mixture of the GABA-receptor agonists muscimol and baclofen. Rats were exposed to the elevated plus maze (EPM to measure effects on anxiety and to the rodent version of the IGT (r-IGT. Inactivation led to increased levels of anxiety on the EPM, while not affecting general activity. The effect in the r-IGT (trials 61-120 was dependent on levels of performance prior to inactivation (trial 41-60: inactivation of the mPFC hampered task-performance in rats, which already showed a preference for the advantageous option, but not in rats which were still choosing in a random manner. These data suggest that the mPFC becomes more strongly involved as rats have learned task-contingencies, i.e. choose for the best long-term option. Furthermore they suggest, along with the data of our earlier study, that both anxiety and decision-making in rats are mediated through a neural circuitry including at least the mPFC. The data are discussed in relation to recent data of rodent studies on the neural circuitry underlying decision-making.

  15. Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo

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    Bettler Bernhard

    2009-11-01

    Full Text Available Abstract Background γ-aminobutyric acid (GABA is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABAA and metabotropic (GABAB receptors. GABAB receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABAB receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABAB receptors is unclear. Results In order to elucidate the functional relevance of GABAB receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABAB(1 subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABAB(1-/- mice. Lack of the GABAB(1 subunit precludes the assembly of functional GABAB receptor. We analyzed SNS-GABAB(1-/- mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABAB(1-/- mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1-/- animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABAB(1 expression in nociceptors. Conclusion This study addressed contribution of GABAB receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABAB agonist was significantly

  16. Effect of gamma-aminobutyric acid B receptor on nitric oxide/nitric oxide synthase system during recurrent febrile seizures%反复热性惊厥过程中γ-氨基丁酸B受体对一氧化氮/一氧化氮合酶体系的调节作用

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    韩颖; 秦炯; 卜定方; 杨志仙; 常杏芝; 杜军保

    2006-01-01

    目的:探讨γ-氨基丁酸B受体(γ-aminobutyric acid B receptor,GABABR)对热性惊厥(febrile seizure,FS)大鼠一氧化氮(nitric oxide,NO)/一氧化氮合酶(nitric oxide synthase,NOS)体系表达的影响.方法:将21 d龄SD大鼠随机分为对照组、FS组、FS+巴氯芬(baclofen)组和FS+法克罗芬(phaclofen)组.采用热水浴诱导大鼠FS,隔日诱导1次,共10次.采用分光光度计法测定大鼠血浆中NO含量;用原位杂交方法观察神经元型一氧化氮合酶(neuronal nitric oxide synthase,nNOS)mRNA表达情况;用免疫组化方法观察nNOS蛋白表达情况.结果:FS+baclofen组NO含量低于FS组[(19.02±9.31)μmol/L比(40.03±9.12)μmol/L],同时nNOS蛋白和mRNA表达也较FS组减弱;而FS+phaclofen组NO含量高于FS组[(66.46±8.15)μmol/L比(40.03±9.12)μmol/L],同时nNOS蛋白和mRNA表达也较FS组增强.结论:反复热性惊厥过程中,GABABR的改变可影响NO/NOS体系的表达.

  17. Effect of 4-aminoantipyrine on gastric compliance and liquid emptying in rats

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    A.M. Vinagre

    2007-07-01

    Full Text Available Dipyrone (Dp delays gastric emptying (GE in rats. There is no information about whether 4-aminoantipyrine (AA, one of its metabolites, has the same effect. The objectives of the present study were to assess the effects of AA and Dp on GE when administered intravenously (iv and intracerebroventricularly (icv (240 µmol/kg and 4 µmol/animal, respectively and on gastric compliance when administered iv (240 µmol/kg. GE was determined in male Wistar rats weighing 250-300 g (5-10 per group after icv or iv injection of the drug by measuring percent gastric retention (GR of a saline meal labeled with phenol red 10 min after administration by gavage. Gastric compliance was estimated in anesthetized rats (10-11 per group, with the construction of volume-pressure curves during intragastric infusion of a saline meal. Compliance was significantly greater in animals receiving Dp (mean ± SEM = 0.26 ± 0.009 mL/mmHg and AA (0.24 ± 0.012 mL/mmHg than in controls (0.19 ± 0.009 mL/mmHg. AA and Dp administered iv significantly increased GR (64.4 ± 2.5 and 54.3 ± 3.8%, respectively compared to control (34 ± 2.2%, a phenomenon observed only with Dp after icv administration. Subdiaphragmatic vagotomy reduced the effect of AA (GR = 31.4 ± 1.5% compared to sham-treated animals. Baclofen, a GABA B receptor agonist, administered icv significantly reduced the effect of AA (GR = 28.1 ± 1.3%. We conclude that Dp and AA increased gastric compliance and AA delayed GE, with the participation of the vagus nerve, through a pathway that does not involve a direct action of the drug on the central nervous system.

  18. Long-term experience with implanted intrathecal drug administration systems for failed back syndrome and chronic mechanical low back pain

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    Treharne GJ

    2002-06-01

    Full Text Available Abstract Background Continuous intrathecal drug delivery has been shown in open studies to improve pain and quality of life in those with intractable back pain who have had spinal surgery. There is limited data on long term effects and and even less for patients with mechanical back pain without prior spinal surgery. Methods We have investigated spinal drug administration systems for patients with failed back syndrome and chronic mechanical low back pain by patient questionnaire study of the efficacy of this therapy and a case notes review. Results 36 patients (97% of 37 approached completed questionnaires, 24 with failed back syndrome and 12 with chronic mechanical low back pain. Recalled pre-treatment levels with current post-treatment levels of pain and a range of quality of life measures (recorded on 11-point numerical rating scales were compared. Pain improved significantly in both groups (Wilcoxan signed ranks test, p 0.005, Wilcoxan signed ranks test with Bonferroni correction. Diamorphine was used in all 37 patients, bupivacaine in 32, clonidine in 27 and baclofen in 3. The mean dose of diamorphine increased for the first 2 years but did not change 2–6 years post implant, averaging 4.5 mg/day. Revision surgery was required in 24% of cases, but reduced to 12% in the later years of our experience. Conclusions We conclude that spinal drug administration systems appear to be of benefit in alleviating pain in the failed back syndrome and chronic mechanical low back pain but need to be examined prospectively.

  19. 乙醇对小鼠不同脑区3H-GABA与GABAA受体结合的影响

    Institute of Scientific and Technical Information of China (English)

    周雪瑞; 李晓煜; 秦晓东; 朱剑琴

    1999-01-01

    采用放射配体受体结合分析法,研究急性注射乙醇对小鼠不同脑区GABAA受体饱和曲线以及与3H-GABA结合的影响.结果表明,急性注射乙醇30min后,GABAA受体饱和曲线出现大幅度上移,乙醇能明显提高3H-GABA与GABAA受体的结合,对小脑、下丘脑、海马及大脑皮层分别提高20%、16%、30%、和28%.乙醇能逆转GGABAA受体拮抗剂如印防己毒素(Picrotoxin)、荷包牡丹碱(Bicuculline)等对受体结合的抑制作用,其中对Pic作用最为显著.戊巴比妥钠(Barbitufal[e)、蝇蕈醇(Muscimol)、氨氧乙酸(Amincoxyacetic acid)在乙醇作用下均不同程度地提高受体的结合量.巴氯芬(Baclofen)对GABAA受体的结合有一定程度的降低作用.说明乙醇能通过提高GABA与GABAA受体的结合,实现对中枢的抑制作用。

  20. Effects of centrally acting antihypertensive drugs on the microcirculation of spontaneously hypertensive rats

    Directory of Open Access Journals (Sweden)

    Estato V.

    2004-01-01

    Full Text Available We investigated the acute effects of centrally acting antihypertensive drugs on the microcirculation of pentobarbital-anesthetized spontaneously hypertensive rats (SHR. The effects of the sympatho-inhibitory agents clonidine and rilmenidine, known to activate both alpha2-adrenoceptors and nonadrenergic I1-imidazoline binding sites (I1BS in the central nervous system, were compared to those of dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H -pyrrol-2-yl-amine hydrochloride (LNP 509, which selectively binds to the I1BS. Terminal mesenteric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 µg, ic induced marked vasoconstriction of the mesenteric microcirculation (27 ± 3%; N = 6, P < 0.05. In contrast, the marked hypotensive and bradycardic effects elicited by intracisternal injection of clonidine (1 µg, rilmenidine (7 µg and LNP 509 (60 µg were accompanied by significant increases in arteriolar diameter (12 ± 1, 25 ± 10 and 21 ± 4%, respectively; N = 6, P < 0.05. The vasodilating effects of rilmenidine and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic inhibition elicited by baclofen (1 µg, ic, a GABA B receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine or exclusively (LNP 509 upon I1BS than with those presenting important alpha2-adrenergic activity (clonidine.

  1. Modulation of the release of norepinephrine by gamma-aminobutyric acid and morphine in the frontal cerebral cortex of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Peoples, R.W.

    1989-01-01

    Agents that enhance gamma-aminobutyric acid, or GABA, neurotransmission modulate certain effects of opioids, such as analgesia. Opioid analgesia is mediated in part by norepinephrine in the forebrain. In this study, the interactions between morphine and GABAergic agents on release of ({sup 3}H) norepinephrine from rat frontal cerebral cortical slices were examined. GABA, 5 {times} 10{sup {minus}5}-10{sup {minus}3} M, enhanced potassium stimulated ({sup 3}H) norepinephrine release and reversed the inhibitory effect of morphine in a noncompetitive manner. GABA did not enhance release of ({sup 3}H) norepinephrine stimulated by the calcium ionophore A23187. The effect of GABA was reduced by the GABA{sub A} receptor antagonists bicuculline methiodide or picrotoxin, and by the selective inhibitor of GABA uptake SKF 89976A, but was blocked completely only when bicuculline methiodide and SKF 89976A were used in combination. The GABA{sub A} agonist muscimol, 10{sup {minus}4} M, mimicked the effect of GABA, but the GABA{sub B} agonist ({plus minus})baclofen, 10{sup {minus}4} M, did not affect the release of ({sup 3}H) norepinephrine in the absence or the presence of morphine. Thus GABA appears to produce this effect by stimulating GABA uptake and GABA{sub A}, but not GABA{sub B}, receptors. In contrast to the results that would be predicted for an event involving GABA{sub A} receptors, however, the effect of GABA did not desensitize, and benzodiazepine agonists did not enhance the effect of GABA at any concentration tested between 10{sup {minus}8} and 10{sup {minus}4} M. Thus these receptors may constitute a subclass of GABA{sub A} receptors. These results support a role of GABA uptake and GABA{sub A} receptors in enhancing the release of norepinephrine and modulating its inhibition by opioids in the frontal cortex of the rat.

  2. An integrative pharmacological approach to radio telemetry and blood sampling in pharmaceutical drug discovery and safety assessment

    Directory of Open Access Journals (Sweden)

    Kamendi Harriet W

    2011-01-01

    Full Text Available Abstract Background A successful integration of the automated blood sampling (ABS and telemetry (ABST system is described. The new ABST system facilitates concomitant collection of physiological variables with blood and urine samples for determination of drug concentrations and other biochemical measures in the same rat without handling artifact. Method Integration was achieved by designing a 13 inch circular receiving antenna that operates as a plug-in replacement for the existing pair of DSI's orthogonal antennas which is compatible with the rotating cage and open floor design of the BASi Culex® ABS system. The circular receiving antenna's electrical configuration consists of a pair of electrically orthogonal half-toroids that reinforce reception of a dipole transmitter operating within the coil's interior while reducing both external noise pickup and interference from other adjacent dipole transmitters. Results For validation, measured baclofen concentration (ABST vs. satellite (μM: 69.6 ± 23.8 vs. 76.6 ± 19.5, p = NS and mean arterial pressure (ABST vs. traditional DSI telemetry (mm Hg: 150 ± 5 vs.147 ± 4, p = NS variables were quantitatively and qualitatively similar between rats housed in the ABST system and traditional home cage approaches. Conclusion The ABST system offers unique advantages over traditional between-group study paradigms that include improved data quality and significantly reduced animal use. The superior within-group model facilitates assessment of multiple physiological and biochemical responses to test compounds in the same animal. The ABST also provides opportunities to evaluate temporal relations between parameters and to investigate anomalous outlier events because drug concentrations, physiological and biochemical measures for each animal are available for comparisons.

  3. PROTECTING EFFECT OF 2-OH-SACLOFEN ON HIPPOCAMPAL NEURONAL ULTRASTRUCTURE OF THE RATS WITH CHRONIC STRESS%2-OH-saclofen对慢性应激大鼠海马神经元超微结构的保护作用

    Institute of Scientific and Technical Information of China (English)

    金玉祥; 姚敏; 程琰; 姜虹; 钟利强

    2005-01-01

    为了观察GABAB受体抑制剂2-OH-saclofen和GABAB受体激动剂baclofen对慢性应激大鼠海马神经元超微结构变化的作用.我们采用足底电击结合噪声的方法制备应激动物模型,同时分别经腹腔注射2-OH-saclofen(100 μg/kg)或baclofen(40mg/kg),应激40 d后取材,在透射电镜下观察海马神经元超微结构的变化,另外采用酶联免疫法检测慢性应激过程中血浆皮质醇含量的变化.结果表明,单纯应激组和应激+baclofen组大鼠海马神经元都有一定的变性改变,如出现了细胞核固缩、线粒体肿胀和线粒体嵴断裂、髓鞘变形,突触结构不清等;而应激+2-OH-saclofen组大鼠海马不同区域的神经元与正常对照组相比无明显改变.单纯应激组和应激+baclofen组血浆皮质醇含量在慢性应激过程中呈升高趋势,而应激+2-OH-saclofen组血浆皮质醇含量在慢性应激过程中呈降低趋势.提示GABAB受体抑制剂2-OH-saclofen对慢性应激大鼠海马神经元有保护作用.

  4. 按压攒竹穴治疗中枢性顽固性呃逆28例分析%A clinical analysis of treating 28 cases of central intractable hiccups by press Cuanzhu point

    Institute of Scientific and Technical Information of China (English)

    张志艳; 连学雷

    2014-01-01

    Objective:To evaluate clinical efficacy and safety of Cuanzhu pressed on intractable hiccups. Methods:60 patients were randomly divided into two groups, 30 cases for each. The treatment was given Cuanzhu point pressed, while the control was given Baclofen. Results: The total efficacy in the treatment was 98.1%, in another it was 81.5%, the difference was statistically significant (P<0.05). Conclusion:The therapy was effective on intractable hiccups, easy to operate with no side reactions.%目的:评价攒竹穴治疗中枢性顽固性呃逆的有效性和安全性。方法:选择60例符合条件的顽固性呃逆患者,将其随机分为治疗组(30例)和对照组(30例),治疗组给予按压攒竹穴治疗,对照组给予巴氯芬治疗。观察两组治疗前后临床症状疗效。结果:治疗组总有效率为98.1%,对照组总有效率为81.5%,两组之间疗效比较,差异有统计学意义(P<0.05)。结论:按压攒竹穴治疗中枢性顽固性呃逆临床疗效确切,且操作简单,无任何副作用。

  5. Statistical design of experiments on fabrication of bilayer tablet of narrow absorption window drug: Development and In vitro characterisation

    Directory of Open Access Journals (Sweden)

    R R Jivani

    2012-01-01

    Full Text Available The current study involves the fabrication of oral bioadhesive bilayer matrices of narrow absorption window drug baclofen and the optimisation of their in vitro drug release and characterisation. Statistical design of experiments, a computer-aided optimisation technique, was used to identify critical factors, their interactions and ideal process conditions that accomplish the targeted response(s. A central composite design was employed to systematically optimise the drug delivery containing a polymer, filler and compression force. The values of ratio of different grades of hydroxypropyl methylcellulose, microcrystalline cellulose and compression force were varied to be fitted in design. Drug release at 1 h (Q 1 , 4 h (Q 4 , 8 h (Q 8 , 12 h (Q 12 , and hardness were taken as responses. Tablets were prepared by direct compression methods. The compressed tablets were evaluated for their hardness, weight variation, friability, content uniformity and diameter. Counter plots were drawn and optimum formulation was selected by desirability function. The formulations were checked for their ex vivo mucoadhesion. The experimental value of Q 1 , Q 4 , Q 8 , Q 12 and hardness for check-point batch was found to be 31.64, 45.82, 73.27, 98.95% and 4.4 kg/cm 2 , respectively. The release profile indicates Highuchi kinetics (Fickian transport mechanism. The results of the statistical analysis of the data demonstrated significant interactions amongst the formulation variables, and the desirability function was demonstrated to be a powerful tool to predict the optimal formulation for the bilayer tablet.

  6. Percutaneous radiofrequency lesions adjacent to the dorsal root ganglion alleviate spasticity and pain in children with cerebral palsy: pilot study in 17 patients

    Directory of Open Access Journals (Sweden)

    van Rhijn Lodewijk W

    2010-06-01

    Full Text Available Abstract Background Cerebral palsy (CP may cause severe spasticity, requiring neurosurgical procedures. The most common neurosurgical procedures are continuous infusion of intrathecal baclofen and selective dorsal rhizotomy. Both are invasive and complex procedures. We hypothesized that a percutaneous radiofrequency lesion of the dorsal root ganglion (RF-DRG could be a simple and safe alternative treatment. We undertook a pilot study to test this hypothesis. Methods We performed an RF-DRG procedure in 17 consecutive CP patients with severe hip flexor/adductor spasms accompanied by pain or care-giving difficulties. Six children were systematically evaluated at baseline, and 1 month and 6 months after treatment by means of the Modified Ashworth Scale (MAS, Gross Motor Function Measure (GMFM and a self-made caregiver's questionnaire. Eleven subsequent children were evaluated using a Visual Analogue Scale (VAS for spasticity, pain and ease of care. Results A total of 19 RF-DRG treatments were performed in 17 patients. We found a small improvement in muscle tone measured by MAS, but no effect on the GMFM scale. Despite this, the caregivers of these six treated children unanimously stated that the quality of life of their children had indeed improved after the RF-DRG. In the subsequent 11 children we found improvements in all VAS scores, in a range comparable to the conventional treatment options. Conclusion RF-DRG is a promising new treatment option for severe spasticity in CP patients, and its definitive effectiveness remains to be defined in a randomised controlled trial.

  7. DM235 (sunifiram): a novel nootropic with potential as a cognitive enhancer.

    Science.gov (United States)

    Ghelardini, C; Galeotti, N; Gualtieri, F; Romanelli, M N; Bucherelli, C; Baldi, E; Bartolini, A

    2002-06-01

    DM235 (sunifiram), a new compound structurally related to piracetam, prevented the amnesia induced by scopolamine (1.5 mg kg(-1) i.p.), after intraperitoneal (0.001-0.1 mg kg(-1)) or oral (0.01-0.1 mg kg(-1)) administration, as shown by a passive avoidance test in mice. The antiamnesic effect of DM235 was comparable to that of well-known nootropic drugs such as piracetam (30-100 mg kg(-1) i.p.), aniracetam (100 mg kg(-1) p.o.) or rolipram (30 mg kg(-1) p.o.). DM235 also prevented mecamylamine (20 mg kg(-1) i.p.)-, baclofen (2 mg kg(-1) i.p.)- and clonidine (0.125 mg kg(-1) i.p.)-induced amnesia in the same test. In the Morris water maze test with rats, scopolamine (0.8 mg kg(-1) i.p.) inhibited the reduction of escape latency in both acquisition and retention/retraining tests. DM235 (0.1 mg kg(-1) i.p.), 20 min before each daily acquisition training, prevented the scopolamine-induced memory impairment. DM235 (1 mg kg(-1) i.p.) also reduced the duration of pentobarbitone-induced hypnosis in mice without modifying the induction time of hypnosis. At the highest effective doses, the investigated compound neither impaired motor coordination (rota-rod test), nor modified spontaneous motility and inspection activity (Animex and hole board tests). These results indicate that DM235, a compound structurally related to piracetam, is a novel nootropic endowed with the capability to prevent cognitive deficits at very low doses. Indeed, its potency is about 1,000 times higher than that of the most active piracetam-like compounds.

  8. The role of medial prefrontal cortex in extinction and reinstatement of alcohol-seeking in rats.

    Science.gov (United States)

    Willcocks, Andrea L; McNally, Gavan P

    2013-01-01

    The prelimbic (PL) and infralimbic (IL) medial prefrontal cortex (mPFC) are thought to play opposing roles in drug-seeking behaviour. Specifically, the PL promotes drug-seeking whereas the IL is necessary for the inhibition of drug-seeking during extinction. We studied the roles of the PL, IL and dorsal peduncular PFC (DP) in the expression of context-induced reinstatement, reacquisition and extinction of alcoholic beer-seeking. In context-induced reinstatement (renewal), animals were trained to nosepoke for alcoholic beer (context A), extinguished (context B) and then tested in context A and B. In reacquisition, animals received the same instrumental training and extinction without any contextual manipulation. On test, alcoholic beer was again available and responding was compared with naive controls. Just prior to the test, rats received bilateral infusion of baclofen/muscimol into the PL, IL or DP. Reversible inactivation of the PL attenuated ABA renewal but augmented reacquisition. Reversible inactivation of IL had no effect on the reinstatement or reacquisition of alcoholic beer-seeking and had no effect on extinction expression (ABB and AAA). IL inactivation did, however, increase the latencies with which animals responded on test but only when animals were tested in the extinction context. DP inactivation had no effect on reinstatement or reacquisition. These studies are inconsistent with the view that PL and IL exert opposing effects on drug-seeking. Rather, they support the view that PL is important for retrieval of drug-seeking contingency information and that the use of contextual information is enhanced with IL manipulation.

  9. Inactivating the infralimbic but not prelimbic medial prefrontal cortex facilitates the extinction of appetitive Pavlovian conditioning in Long-Evans rats.

    Science.gov (United States)

    Mendoza, J; Sanio, C; Chaudhri, N

    2015-02-01

    The infralimbic medial prefrontal cortex (IL) has been posited as a common node in distinct neural circuits that mediate the extinction of appetitive and aversive conditioning. However, appetitive extinction is typically assessed using instrumental conditioning procedures, whereas the extinction of aversive conditioning is customarily studied using Pavlovian assays. The role of the IL in the extinction of appetitive Pavlovian conditioning remains underexplored. We investigated the involvement of the IL and prelimbic medial prefrontal cortex (PrL) in appetitive extinction in Pavlovian and instrumental conditioning assays in male, Long-Evans rats. Following acquisition, a gamma-aminobutyric acid agonist solution (0.03 nmol muscimol; 0.3 nmol baclofen; 0.3 μl/side) was bilaterally microinfused into the IL or PrL to pharmacologically inactivate each region before the first extinction session. Compared to saline, PrL inactivation did not affect the acquisition of extinction or the recall of extinction memory 24-h later. IL inactivation caused a more rapid extinction of Pavlovian conditioning, but had no effect on the extinction of instrumental conditioning or extinction recall. IL inactivation during a Pavlovian conditioning session in which conditioned stimulus (CS) trials were paired with sucrose did not affect CS-elicited behaviour, but increased responding during intervals that did not contain the CS. The same manipulation did not impact lever pressing for sucrose. These findings suggest that the IL may normally maintain Pavlovian conditioned responding when an anticipated appetitive CS is unexpectedly withheld, and that this region has distinct roles in the expression of Pavlovian conditioning when an appetitive unconditioned stimulus is either presented or omitted.

  10. Allosteric modulation of GABA(B) receptor function in human frontal cortex.

    Science.gov (United States)

    Olianas, Maria C; Ambu, Rossano; Garau, Luciana; Onali, Pierluigi

    2005-01-01

    In the present study, the effects of different allosteric modulators on the functional activity of gamma-aminobutyric acid (GABA)B receptors in membranes of post-mortem human frontal cortex were examined. Western blot analysis indicated that the tissue preparations expressed both GABA(B1) and GABA(B2) subunits of the GABA(B) receptor heterodimer. In [35S]-GTPgammaS binding assays, Ca2+ ion (1 mM) enhanced the potency of the agonists GABA and 3-aminopropylphosphinic acid (3-APA) and that of the antagonist CGP55845, but not that of the GABA(B) receptor agonist (-)-baclofen. CGP7930 (2,6-di-t-Bu-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol), a positive allosteric modulator of GABA(B) receptors, potentiated both GABA(B) receptor-mediated stimulation of [35S]-GTPgammaS binding and inhibition of forskolin (FSK)-stimulated adenylyl cyclase activity. Chelation of Ca2+ ion by EGTA reduced the CGP7930 enhancement of GABA potency in stimulating [35S]-GTPgammaS binding by two-fold. Fendiline, also reported to act as a positive allosteric modulator of GABA(B) receptors, failed to enhance GABA stimulation of [35S]-GTPgammaS binding but inhibited the potentiating effect of CGP7930. The inhibitory effect was mimicked by the phenothiazine antipsychotic trifluoperazine (TFP), but not by other compounds, such as verapamil or diphenydramine (DPN). These data demonstrate that the function of GABA(B) receptors of human frontal cortex is positively modulated by Ca2+ ion and CGP7930, which interact synergistically. Conversely, fendiline and trifluoperazine negatively affect the allosteric regulation by CGP7930.

  11. GABAB receptors in the NTS mediate the inhibitory effect of trigeminal nociceptive inputs on parasympathetic reflex vasodilation in the rat masseter muscle.

    Science.gov (United States)

    Ishii, Hisayoshi; Izumi, Hiroshi

    2012-03-15

    The present study was designed to examine whether trigeminal nociceptive inputs are involved in the modulation of parasympathetic reflex vasodilation in the jaw muscles. This was accomplished by investigating the effects of noxious stimulation to the orofacial area with capsaicin, and by microinjecting GABA(A) and GABA(B) receptor agonists or antagonists into the nucleus of the solitary tract (NTS), on masseter hemodynamics in urethane-anesthetized rats. Electrical stimulation of the central cut end of the cervical vagus nerve (cVN) in sympathectomized animals bilaterally increased blood flow in the masseter muscle (MBF). Increases in MBF evoked by cVN stimulation were markedly reduced following injection of capsaicin into the anterior tongue in the distribution of the lingual nerve or lower lip, but not when injected into the skin of the dorsum of the foot. Intravenous administration of either phentolamine or propranolol had no effect on the inhibitory effects of capsaicin injection on the increases of MBF evoked by cVN stimulation, which were largely abolished by microinjecting the GABA(B) receptor agonist baclofen into the NTS. Microinjection of the GABA(B) receptor antagonist CGP-35348 into the NTS markedly attenuated the capsaicin-induced inhibition of MBF increase evoked by cVN stimulation, while microinjection of the GABA(A) receptor antagonist bicuculline did not. Our results indicate that trigeminal nociceptive inputs inhibit vagal-parasympathetic reflex vasodilation in the masseter muscle and suggest that the activation of GABA(B) rather than GABA(A) receptors underlies the observed inhibition in the NTS.

  12. GABAB R活性水平对致痫大鼠认知功能及Arc/Arg3.1表达的影响%Effects of GABAB receptor expression level on cognitive impairment and Arc/Arg3.1 expression in induced epileptic rats model

    Institute of Scientific and Technical Information of China (English)

    兰彦平; 孙涛; 张春; 袁聪聪; 杨征; 王峰

    2016-01-01

    目的 探讨GABABR活性变化对癫痫大鼠认知功能及Arc/Arg3.1的影响.方法 建立氯化锂-匹罗卡品致痫模型,随机分成正常组、巴氯酚组、CGP组、单纯点燃组.避暗、水迷宫实验观察大鼠认知情况,免疫组化、荧光定量PCR、免疫印迹检测海马组织内GABABR(GB1、GB2)、Arc/Arg3.1蛋白及mRNA表达情况.结果 避暗实验:4组大鼠穿梭次数为:6.8±0.6、1.2土0.2、5.4±0.5及3.6±0.3,潜伏期为:26.1 ±3.9、152.2±12.9、65.8 ±7.0、91.2±9.1,与水迷宫行为学变化趋势一致,显示致痫大鼠认知功能减退,巴氯酚进一步抑制致痫大鼠学习和记忆获取能力,CGP35348可改善致痫大鼠认知功能.Arc/Arg3.1及GB1、GB2相对表达量检测显:致痫大鼠较正常大鼠Arc/Arg3.1及GB1、GB2表达量明显增高,致痫组大鼠相对比,巴氯酚组Arc/Arg3.1表达量下降,GB1、GB2增高;而CGP35348组Arc/Arg3.1表达量增高,GB1、GB2降低.结论 GABABR活性水平可以调控Arc/Arg3.1表达,并影响致痫大鼠认知功能.%Objective To investigate the effects of GABAB receptor on cognitive impairment by using pilocarpine induced kindled rats model and also to check early gene (Arc/Arg3.1) expression.Methods Pilocarpine induced kindled rats were divided into four groups (Group normal,Baclofen,CGP and Kindled) randomly,and every group included 20 rats.We checked their cognitive impairment by using passive avoidance test and water maze test.The expression of GABAB receptor (GB1,GB2) and Arc/Arg3.1 was tested by immunohistochemical staining,RT-PCR and Western blot.Results Passive avoidance test showed four Group rats shuttle times were 6.8 ± 0.6,1.2 ± 0.2,5.4 ± 0.5,3.6 ± 0.3,incubation period were 26.1 ±3.9,152.2 ± 12.9,65.8 ±7.0,91.2 ±9.1,and water maze test had the same trend,with values in epilepsy groups significantly lower than the normal group of rats,which meant cognitive dysfunction.The above results also showed Baclofen further inhibited the learning

  13. 大鼠生后MGBv神经元主动膜特性的变化及GABA受体激动剂的影响%Alteration of membrane properties of MGBv neurons and the effect of GABA receptor agonist on them during postnatal development in rats

    Institute of Scientific and Technical Information of China (English)

    姚小红; 万子兵; 熊鹰

    2005-01-01

    Objective To observe membrane properties of ventral partition of the medial geniculate body (MGBv) in Wistar rat and the effect of GABA receptor agonist on them during postnatal development. Methods Whole-cell patch clamp recording was used to record waveform of action potential (AP) and the effect of GABA receptor agonist on them from neurons in the MGBv of rats ( postnatal days 3-30). Results There was a difference in AP firing pattern in rat MGBv neurons of different postnatal day. We only recorded low threshold Ca2+ spikes (LTS) in P3 MGBv neurons, but recorded AP in P6-30 MGBv neurons after depolarizing currents application; AP was recorded at the start phase of pulse and with a long-last after hyperpolarization potential (AHP) in P8, in P20 AP was recorded after a delay and it appeared on depolarizing ramp with a shorter-last AHP compared with P8. The GABAA receptor agonist, muscimol, and the GABAB receptor agonist, baclofen, had effects on responses evoked by depolarizing current in the MGBv neurons in P6 and P15 rats. Muscimol and baclofen reduced AP firing rather than AP amplitude in P6 MGBv neurons, however, in P15 MGBv neurons baclofen had little effect on AP firing while muscimol greatly reduced the size of voltage shift produced by positive or negative current injection. Conclusion The AP waveform of MGBv neurons matures rapidly during first two postnatal weeks. A similar rapid maturation also has been observed in rat neocortical and hippocampal pyramidal neurons as well as in ferret dorsal lateral geniculate nucleus (LGNd) neurons. These results suggest that in the central nervous system of small mammals, AP waveforms mature rapidly in many types of neurons, thus, coordinated activities in neuronal circuits may occur. In early postnatal development, GABA receptor mainly mediates an excitation effect, depolarizes P6 MGBv neurons and dramatically increases the frequency of AP firing. Inhibition of GABA receptor matures slowly along with increment of

  14. Hypoxanthine-guanine phosophoribosyltransferase (HPRT deficiency: Lesch-Nyhan syndrome

    Directory of Open Access Journals (Sweden)

    Puig Juan G

    2007-12-01

    lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments.

  15. Distonias: aspectos terapêuticos Dystonias: therapeutic aspects

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    João Carlos Papaterra Limongi

    1996-03-01

    Full Text Available Diversas abordagens terapêuticas são utilizadas em pacientes com distonias. Sempre que possível, causas específicas devem ser identificadas e tratadas. As modalidades de tratamento sintomático podem ser agrupadas em três categorias: tratamento farmacológico, cirúrgico e injeções locais de toxina botulínica. Cada uma dessas modalidades apresenta algumas vantagens e limitações. Formas generalizadas, particularmente as de ocorrência na infância, podem se beneficiar com drogas anticolinérgicas ou, em alguns casos, com a levodopa ou outros agentes tais como antagonistas da dopamina, baclofeno e benzodiazepínicos. As formas focais não respondem adequadamente ao tratamento farmacológico sistêmico mas beneficiam-se significativamente com injeções de toxina botulínica nos grupos musculares acometidos. Cerca de 90% dos pacientes com blefarospasmo e 70% daqueles com distonia cervical apresentam resposta satisfatória a esse tipo de terapia. O tratamento cirúrgico tem sido utilizado em algumas formas de distonias generalizadas (lesões estereotáxicas, axiais (rizotomias ou focais (miectomias e neurectomias com resultados variáveis.Several approaches have been employed for the treatment of dystonias. Possible specific causes should be searched for and specific treatment should be instituted. Different types of symptomatic treatment are grouped according to the following categories: pharmacological systemic therapy, surgical therapy and botulinum toxin injections in the affected muscles. Each of these approaches has its advantages and limitations. Generalized dystonias should be treated with anticholinergic agents. In some cases, levodopa or other drugs such as dopamine antagonists, baclofen and benzodiazepines should be preferred. Focal dystonias respond dramatically to local injections of botulinum toxin. Over 90% of patients with blepharospasm and 70% of patients with cervical dystonia present a satisfactory response to this

  16. Medial Prefrontal Cortex Involvement in the Expression of Extinction and ABA Renewal of Instrumental Behavior for a Food Reinforcer

    Science.gov (United States)

    Eddy, Meghan C.; Todd, Travis P.; Bouton, Mark E.; Green, John T.

    2015-01-01

    Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of

  17. Sedative and hypothermic effects of gamma-hydroxybutyrate (GHB) in rats alone and in combination with other drugs: assessment using biotelemetry.

    Science.gov (United States)

    van Nieuwenhuijzen, Petra S; McGregor, Iain S

    2009-08-01

    The recreational drug gamma-hydroxybutyrate (GHB) has euphoric effects and can induce sedation and body temperature changes. GHB is frequently combined with other recreational drugs although these interactions are not well characterised. The present study used biotelemetry to provide a fine-grained analysis of the effects of GHB on body temperature and locomotor activity in freely moving rats, and investigated interactions between GHB and 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH) and various antagonist drugs. GHB (1000mg/kg) caused profound sedation for more than 2h and a complex triphasic effect on body temperature: an initial hypothermia (5-40min), followed by hyperthermia (40-140min), followed again by hypothermia (140-360min). A lower GHB dose (500mg/kg) also caused sedation but only a hypothermic effect that lasted up to 6h. The dopamine D(1) receptor antagonist SCH 23390 (1mg/kg), the opioid antagonist naltrexone (1mg/kg), the benzodiazepine antagonist flumazenil (10mg/kg), and the 5-HT(2A/2C) receptor antagonist ritanserin (1mg/kg) did not prevent the overall sedative or body temperature effects of GHB (1000mg/kg). However the GABA(B) antagonist SCH 50911 (50mg/kg) prevented the hyperthermia induced by GHB (1000mg/kg). Repeated daily administration of GHB (1000mg/kg) produced tolerance to the sedative and hyperthermic effects of the drug and cross-tolerance to the sedative effects of the GABA(B) receptor agonist baclofen (10mg/kg). A high ambient temperature of 28 degrees C prevented the hypothermia obtained with GHB (500mg/kg) at 20 degrees C, while GHB (500mg/kg) reduced the hyperthermia and hyperactivity produced by co-administered doses of MDMA (5mg/kg) or METH (1mg/kg) at 28 degrees C. These results further confirm a role for GABA(B) receptors in the hypothermic and sedative effects of GHB and show an interaction between GHB and MDMA, and GHB and METH, that may be relevant to the experience of recreational users who mix these

  18. Regional Fos-expression induced by γ-hydroxybutyrate (GHB): comparison with γ-butyrolactone (GBL) and effects of co-administration of the GABAB antagonist SCH 50911 and putative GHB antagonist NCS-382.

    Science.gov (United States)

    van Nieuwenhuijzen, P S; McGregor, I S; Chebib, M; Hunt, G E

    2014-09-26

    γ-Hydroxybutyrate (GHB) has a complex array of neural actions that include effects on its own high-affinity GHB receptor, the release of neuroactive steroids, and agonist actions at GABAA and GABAB receptors. We previously reported partial overlap in the c-Fos expression patterns produced by GHB and the GABAB agonist, baclofen in rats. The present study extends these earlier findings by examining the extent to which GHB Fos expression and behavioral sedation are prevented by (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), a GABAB antagonist, and NCS-382, a putative antagonist at the high-affinity GHB receptor. We also compare Fos expression caused by GHB and its precursor γ-butyrolactone (GBL), which is a pro-drug for GHB but lacks the high sodium content of the parent GHB molecule. Both GHB (1,000 mg/kg) and GBL (600 mg/kg) induced rapid sedation in rats that lasted over 90 min and caused similar Fos expression patterns, albeit with GBL causing greater activation of the nucleus accumbens (core and shell) and dentate gyrus (granular layer). Pretreatment with SCH 50911 (100mg/kg) partly reversed the sedative effects of GHB and significantly reduced GHB-induced Fos expression in only four regions: the tenia tecta, lateral habenula, dorsal raphe and laterodorsal tegmental nucleus. NCS-382 (50mg/kg) had no effect on GHB-induced sedation or Fos expression. When given alone, both NCS-382 and SCH 50911 increased Fos expression in the bed nucleus of the stria terminalis, central amygdala, parasubthalamic nucleus and nucleus of the solitary tract. SCH 50911 alone affected the Islands of Calleja and the medial, central and paraventricular thalamic nuclei. Overall, this study shows a surprising lack of reversal of GHB-induced Fos expression by two relevant antagonists, both of which have marked intrinsic actions. This may reflect the limited doses tested but also suggests that GHB Fos expression reflects mechanisms independent of GHB and GABAB receptors.

  19. Effects of GABA agonists on body temperature regulation in GABA(B(1))-/- mice.

    Science.gov (United States)

    Quéva, Christophe; Bremner-Danielsen, Marianne; Edlund, Anders; Ekstrand, A Jonas; Elg, Susanne; Erickson, Sven; Johansson, Thore; Lehmann, Anders; Mattsson, Jan P

    2003-09-01

    1. Activation of GABA(B) receptors evokes hypothermia in wildtype (GABA(B(1))+/+) but not in GABA(B) receptor knockout (GABA(B(1))-/-) mice. The aim of the present study was to determine the hypothermic and behavioural effects of the putative GABA(B) receptor agonist gamma-hydroxybutyrate (GHB), and of the GABA(A) receptor agonist muscimol. In addition, basal body temperature was determined in GABA(B(1))+/+, GABA(B(1))+/- and GABA(B(1))-/- mice. 2. GABA(B(1))-/- mice were generated by homologous recombination in embryonic stem cells. Correct gene targeting was assessed by Southern blotting, PCR and Western blotting. GABA(B) receptor-binding sites were quantified with radioligand binding. Measurement of body temperature was done using subcutaneous temperature-sensitive chips, and behavioural changes after drug administration were scored according to a semiquantitative scale. 3. GABA(B(1))-/- mice had a short lifespan, probably caused by generalised seizure activity. No histopathological or blood chemistry changes were seen, but the expression of GABA(B(2)) receptor protein was below the detection limit in brains from GABA(B(1))-/- mice, in the absence of changes in mRNA levels. 4. GABA(B) receptor-binding sites were absent in brain membranes from GABA(B(1))-/- mice. 5. GABA(B(1))-/- mice were hypothermic by approximately 1 degrees C compared to GABA(B(1))+/+ and GABA(B(1))+/- mice. 6. Injection of baclofen (9.6 mg kg-1) produced a large reduction in body temperature and behavioural effects in GABA(B(1))+/+ and in GABA(B(1))+/- mice, but GABA(B(1))-/- mice were unaffected. The same pattern was seen after administration of GHB (400 mg kg-1). The GABA(A) receptor agonist muscimol (2 mg kg-1), on the other hand, produced a more pronounced hypothermia in GABA(B(1))-/-mice. In GABA(B(1))+/+ and GABA(B(1))+/- mice, muscimol induced sedation and reduced locomotor activity. However, when given to GABA(B(1))-/- mice, muscimol triggered periods of intense jumping and wild

  20. Effects of transient oxygen-glucose deprivation on G-proteins and G-protein-coupled receptors in rat CA3 pyramidal cells in vitro.

    Science.gov (United States)

    Tanabe, M; Gähwiler, B H; Gerber, U

    1998-06-01

    The role of guanosine triphosphate-binding proteins (G-proteins) in the generation of the outward current during transient oxygen-glucose deprivation (OGD) was investigated in CA3 pyramidal cells in rat hippocampal organotypic slice cultures using the single-electrode voltage-clamp technique with KMeSO4-filled microelectrodes. To simulate ischaemia, brief chemical OGD (2 mM 2-deoxyglucose and 3 mM NaN3 for 4-9 min) was used, which induced an outward K+ current associated with an increase in input conductance. OGD failed to induce the outward current under conditions where G-protein function was disrupted by loading cells with guanosine 5'-O-(2-thiodiphosphate) [GDPbetaS] or after prolonged injection of guanosine 5'-O(3-thiotdphosphate) [GTPgammaS]. However, in slices treated with pertussis toxin (PTX), OGD still elicited the outward current, indicating that PTX-insensitive G-proteins are involved. Consistent with this insensitivity to PTX, neither adenosine receptors nor GABA(B) (gamma-aminobutyric acid) receptors, which operate via PTX-sensitive G-proteins, mediate the OGD-induced outward current. When adenosine receptors or GABA(B) receptors were blocked with 1,3-dipropyl-8-psulphophenylxanthine (DPSPX, 5 microM) or CGP 52 432 (10 microM), respectively, the OGD-induced response was not modified. The response also persisted following pretreatment of slice cultures with tetanus toxin to prevent vesicular release of neurotransmitters and neuromodulators from presynaptic terminals. Both PTX-sensitive and PTX-insensitive G-protein-mediated responses were suppressed during OGD. The inward current induced by the metabotropic glutamate receptor agonist 1 S, 3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) and the outward current elicited by adenosine or baclofen were strongly or completely attenuated. In contrast, the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) response was not affected. These findings suggest that during OGD there is

  1. Alcohol abuse and related disorders treatment of alcohol dependence

    Directory of Open Access Journals (Sweden)

    Yu. P. Sivolap

    2014-01-01

    medications, including baclofen, gabapentin, pregabalin, ondansetron, modafinil, and aripiprazole, are able to decrease alcoholic needs and to alleviate the manifestations of alcohol dependence. The Russian narcological practice in using antipsychotics to suppress a craving for alcohol (as well as other psychoactive substances contradicts the principles of evidence-based medicine and has no scientific base.

  2. Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence

    Science.gov (United States)

    Campbell, Erin J.; Whitaker, Leslie R.; Harvey, Brandon K.; Kaganovsky, Konstantin; Adhikary, Sweta; Hope, Bruce T.; Heins, Robert C.; Prisinzano, Thomas E.; Vardy, Eyal; Bonci, Antonello; Bossert, Jennifer M.

    2016-01-01

    In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse. SIGNIFICANCE STATEMENT In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol

  3. Ongoing behavioral state information signaled in the lateral habenula guides choice flexibility in freely moving rats

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    Phillip Michael Baker

    2015-11-01

    Full Text Available The lateral habenula (LHb plays a role in a wide variety of behaviors ranging from maternal care, to sleep, to various forms of cognition. One prominent theory with ample supporting evidence is that the LHb serves to relay basal ganglia and limbic signals about negative outcomes to midbrain monoaminergic systems. This makes it likely that the LHb is critically involved in behavioral flexibility as all of these systems have been shown to contribute when flexible behavior is required. Behavioral flexibility is commonly examined across species and is impaired in various neuropsychiatric conditions including autism, depression, addiction, and schizophrenia; conditions in which the LHb is thought to play a role. Therefore, a thorough examination of the role of the LHb in behavioral flexibility serves multiple functions including understanding possible connections with neuropsychiatric illnesses and additional insight into its role in cognition in general. Here we assess the LHb’s role in behavioral flexibility through comparisons of the roles its afferent and efferent pathways are known to play. Additionally, we provide new evidence supporting the LHb contributions to behavioral flexibility through organization of specific goal directed actions under cognitively demanding conditions. Specifically, in the first experiment, a majority of neurons recorded from the LHb were found to correlate with velocity on a spatial navigation task and did not change significantly when reward outcomes were manipulated. Additionally, measurements of local field potential in the theta band revealed significant changes in power relative to velocity and reward location. In a second set of experiments, inactivation of the LHb with the GABA agonists baclofen and muscimol led to an impairment in a spatial/response based repeated probabilistic reversal learning task. Control experiments revealed that this impairment was likely due to the demands of repeated switching

  4. Combinational spinal GAD65 gene delivery and systemic GABA-mimetic treatment for modulation of spasticity.

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    Osamu Kakinohana

    Full Text Available BACKGROUND: Loss of GABA-mediated pre-synaptic inhibition after spinal injury plays a key role in the progressive increase in spinal reflexes and the appearance of spasticity. Clinical studies show that the use of baclofen (GABA(B receptor agonist, while effective in modulating spasticity is associated with major side effects such as general sedation and progressive tolerance development. The goal of the present study was to assess if a combined therapy composed of spinal segment-specific upregulation of GAD65 (glutamate decarboxylase gene once combined with systemic treatment with tiagabine (GABA uptake inhibitor will lead to an antispasticity effect and whether such an effect will only be present in GAD65 gene over-expressing spinal segments. METHODS/PRINCIPAL FINDINGS: Adult Sprague-Dawley (SD rats were exposed to transient spinal ischemia (10 min to induce muscle spasticity. Animals then received lumbar injection of HIV1-CMV-GAD65 lentivirus (LVs targeting ventral α-motoneuronal pools. At 2-3 weeks after lentivirus delivery animals were treated systemically with tiagabine (4, 10, 20 or 40 mg/kg or vehicle and the degree of spasticity response measured. In a separate experiment the expression of GAD65 gene after spinal parenchymal delivery of GAD65-lentivirus in naive minipigs was studied. Spastic SD rats receiving spinal injections of the GAD65 gene and treated with systemic tiagabine showed potent and tiagabine-dose-dependent alleviation of spasticity. Neither treatment alone (i.e., GAD65-LVs injection only or tiagabine treatment only had any significant antispasticity effect nor had any detectable side effect. Measured antispasticity effect correlated with increase in spinal parenchymal GABA synthesis and was restricted to spinal segments overexpressing GAD65 gene. CONCLUSIONS/SIGNIFICANCE: These data show that treatment with orally bioavailable GABA-mimetic drugs if combined with spinal-segment-specific GAD65 gene overexpression can

  5. Uptake of 3-[{sup 125}I]iodo-{alpha}-methyl-L-tyrosine into colon cancer DLD-1 cells: characterization and inhibitory effect of natural amino acids and amino acid-like drugs

    Energy Technology Data Exchange (ETDEWEB)

    Shikano, Naoto [Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan)], E-mail: sikano@ipu.ac.jp; Ogura, Masato [Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Okudaira, Hiroyuki [School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa 920-0942 (Japan); Nakajima, Syuichi; Kotani, Takashi [Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Kobayashi, Masato [School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa 920-0942 (Japan); Nakazawa, Shinya [Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Baba, Takeshi; Yamaguchi, Naoto [Center for Medical Sciences, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Kubota, Nobuo [Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Iwamura, Yukio [Center for Humanities and Sciences, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Kawai, Keiichi [School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa 920-0942 (Japan)

    2010-02-15

    Introduction: We examined 3-[{sup 123}I]iodo-{alpha}-methyl-L-tyrosine ([{sup 123}I]IMT) uptake and inhibition by amino acids and amino acid-like drugs in the human DLD-1 colon cancer cell line, to discuss correlation between the inhibition effect and structure. Methods: Expression of relevant neutral amino acid transporters was examined by real-time PCR with DLD-1 cells. The time course of [{sup 125}I]IMT uptake, contributions of transport systems, concentration dependence and inhibition effects by amino acids and amino acid-like drugs (1 mM) on [{sup 125}I]IMT uptake were examined. Results: Expression of system L (4F2hc, LAT1 and LAT2), system A (ATA1, ATA2) and system ASC (ASCT1) was strongly detected; system L (LAT3, LAT4) and MCT8 were weakly detected; and B{sup 0}AT was not detected. [{sup 125}I]IMT uptake in DLD-1 cells involved Na{sup +}-independent system L primarily and Na{sup +}-dependent system(s). Uptake of [{sup 125}I]IMT in Na{sup +}-free buffer followed Michaelis-Menten kinetics, with a K{sub m} of 78 {mu}M and V{sub max} of 333 pmol/10{sup 6} cells per minute. Neutral D- and L-amino acids with branched or aromatic large side chains inhibited [{sup 125}I]IMT uptake. Tyrosine analogues, tryptophan analogues, L-phenylalanine and p-halogeno-L-phenylalanines, and gamma amino acids [including 3,4-dihydroxy-L-phenylalanine (L-DOPA), DL-threo-{beta}-(3,4-dihydroxyphenyl)serine (DOPS), 4-[bis(2-chloroethyl)amino]-L-phenylalanine and 1-(aminomethyl)-cyclohexaneacetic acid] strongly inhibited [{sup 125}I]IMT uptake, but L-tyrosine methyl ester and R(+)/S(-)-baclofen weakly inhibited uptake. The substrates of system ASC and A did not inhibit [{sup 125}I]IMT uptake except L-serine and D/L-cysteine. Conclusions: [{sup 125}I]IMT uptake in DLD-1 cells involves mostly LAT1 and its substrates' (including amino acid-like drugs derived from tyrosine, tryptophan and phenylalanine) affinity to transport via LAT1. Whether transport of gamma amino acid analogues is

  6. 脑缺血激活氯苯氨丁酸对ORP150蛋白及海马CA1区神经元的影响

    Institute of Scientific and Technical Information of China (English)

    陈群娥; 何艳芳; 张文辉; 徐艳; 王军; 王文静

    2013-01-01

    目的:探讨脑缺血激活氯苯氨丁酸(baclofen)对氧调节蛋白150(Oxygen-regulated proteins,ORP150)表达量及海马CA1区神经元的影响。方法:四动脉结扎建立大鼠全脑缺血模型,实验动物随机分为假手术组、缺血再灌注组(I/R)、溶剂对照组、氯苯氨丁酸(baclofen)处理组;缺血5min后腹腔注射baclofen 20mg/kg,Western blot法检测大鼠海马CA1区OPR150和Bcl-2的表达情况;NeuN染色和TUNEL法分别观察海马CA1区神经元的存活和凋亡情况。结果:缺血再灌注30min,baclofen处理组的OPR150蛋白表达水平较I/R组显著升高(P<0.05);缺血再灌注6h,baclofen处理组的Bcl-2蛋白表达水平较I/R组显著升高(P<0.05)。baclofen处理组海马CA1区存活神经元细胞较I/R组明显增加(P<0.05),其凋亡样损伤神经元较I/R组显著减少(P<0.05)。结论:氯苯氨丁酸通过增强OPR150蛋白表达水平来减少脑缺血诱导的神经细胞凋亡。

  7. Development of spasticity with age in a total population of children with cerebral palsy

    Directory of Open Access Journals (Sweden)

    Wagner Philippe

    2008-11-01

    Full Text Available Abstract Background The development of spasticity with age in children with cerebral palsy (CP has, to our knowledge, not been studied before. In 1994, a register and a health care program for children with CP in southern Sweden were initiated. In the programme the child's muscle tone according to the modified Ashworth scale is measured twice a year until six years of age, then once a year. We have used this data to analyse the development of spasticity with age in a total population of children with cerebral palsy. Methods All measurements of muscle tone in the gastrocnemius-soleus muscle in all children with CP from 0 to 15 years during the period 1995–2006 were analysed. The CP subtypes were classified according to the Surveillance of Cerebral Palsy in Europe network system. Using these criteria, the study was based on 6218 examinations in 547 children. For the statistical analysis the Ashworth scale was dichotomized. The levels 0–1 were gathered in one category and levels 2–4 in the other. The pattern of development with age was evaluated using piecewise logistic regression in combination with Akaike's An Information Criterion. Results In the total sample the degree of muscle tone increased up to 4 years of age. After 4 years of age the muscle tone decreased each year up to 12 years of age. A similar development was seen when excluding the children operated with selective dorsal rhizotomy, intrathecal baclofen pump or tendo Achilles lengthening. At 4 years of age about 47% of the children had spasticity in their gastro-soleus muscle graded as Ashworth 2–4. After 12 years of age 23% of the children had that level of spasticity. The CP subtypes spastic bilateral and spastic unilateral CP showed the same pattern as the total sample. Children with dyskinetic type of CP showed an increasing muscle tone up to age 6, followed by a decreasing pattern up to age 15. Conclusion In children with CP, the muscle tone as measured with the Ashworth

  8. Current responses mediated by endogenous GABAB and GABAC receptors in Xenopus oocytes%非洲爪蟾卵母细胞GABAB和GABAC受体介导的电流反应

    Institute of Scientific and Technical Information of China (English)

    杨青; 李之望; 魏劲波

    2001-01-01

    实验应用双电极电压箝技术,在具有滤泡膜的非洲爪蟾(Xenopuslaevis)卵母细胞上记录到γ-氨基丁酸(γ-aminobutyricacid,GABA)-激活电流。此GABA-激活电流的特点及有关GABA受体类型的研究和分析如下:(1)在35.5%(55/155)的受检细胞外加GABA可引起一慢的浓度依赖性的外向电流。(2)GABAA受体的选择性拮抗剂bicuculline(10-5mol/L)对GABA(10-5mol/L)引起的外向电流无阻断作用(n=6)。(3)GABAB受体的选择性拮抗剂2-hydroxysaclofen(10-4mol/L)能将GABA(10-5mol/L)引起的外向电流可逆性地转变为内向电流,后者又可被GABAC受体的选择性拮抗剂I4AA(10-5mol/L)所消除(n=6)。(4)GABAB受体的特异性激动剂baclofen可引起部分(20%,12/60)受检细胞产生一慢的浓度依赖性的外向电流。3×10-6、3×10-5及3×10-4mol/L2-hydroxysaclofen分别阻断baclofen(10-5mol/L)-激活电流(6.3±3.2)%,(44.1±2.2)%及(86.0±1.6)%(n=6)。(5)baclofen激活电流的I-V曲线显示逆转电位在-96.8±7.2mV左右,此电流可分别被TEA(5mmol/L)和BaCl2(2mmol/L)所阻断。以上结果提示:在非洲爪蟾的卵母细胞上存在内源性GABAB和GABAC受体,GABAB受体介导的为外向电流,而GABAC受体介导的为内向电流。

  9. Medial prefrontal cortex involvement in the expression of extinction and ABA renewal of instrumental behavior for a food reinforcer.

    Science.gov (United States)

    Eddy, Meghan C; Todd, Travis P; Bouton, Mark E; Green, John T

    2016-02-01

    Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of

  10. New developments in the management of narcolepsy

    Directory of Open Access Journals (Sweden)

    Abad VC

    2017-03-01

    investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA modulation with GABAA receptor agonists clarithromycin and flumazenil may help daytime somnolence. Other drugs investigated include GABAB agonists (baclofen, melanin-concentrating hormone antagonist, and thyrotropin-releasing hormone agonists. Hypocretin-based therapies include hypocretin peptide replacement administered either through an intracerebroventricular route or intranasal route. Hypocretin neuronal transplant and transforming stem cells into hypothalamic neurons are also discussed in this article. Immunotherapy to prevent hypocretin neuronal death is reviewed. Keywords: narcolepsy, cataplexy, emerging treatment, sodium oxybate, pitolisant, JZP-110, hypocretin peptide, immunotherapy 

  11. Ontogenesis of presynaptic GABAB receptor-mediated inhibition in the CA3 region of the rat hippocampus.

    Science.gov (United States)

    Caillard, O; McLean, H A; Ben-Ari, Y; Gaïarsa, J L

    1998-03-01

    gamma-Aminobutyric acid-B(GABAB) receptor-dependent and -independent components of paired-pulse depression (PPD) were investigated in the rat CA3 hippocampal region. Intracellular and whole cell recordings of CA3 pyramidal neurons were performed on hippocampal slices obtained from neonatal (5-7 day old) and adult (27-34 day old) rats. Electrical stimulation in the hilus evoked monosynaptic GABAA postsynaptic currents (eIPSCs) isolated in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and D(-)2-amino-5-phosphovaleric acid (-AP5, 50 microM) with 2(triethylamino)-N-(2,6-dimethylphenyl) acetamine (QX314) filled electrodes. In adult CA3 pyramidal neurons, when a pair of identical stimuli was applied at interstimulus intervals (ISIs) ranging from 50 to 1,500 ms the amplitude of the second eIPSC was depressed when compared with the first eIPSC. This paired-pulse depression (PPD) was partially blocked by P-3-aminoprophyl -P-diethoxymethylphosphoric acid (CGP35348, 0.5 mM), a selective GABAB receptor antagonist. In neonates, PPD was restricted to ISIs shorter than 200 ms and was not affected by CGP35348. The GABAB receptor agonist baclofen reduced the amplitude of eIPSCs in a dose-dependent manner with the same efficiency in both adults and neonates. Increasing the probability of transmitter release with high Ca2+ (4 mM)/low Mg2+ (0.3 mM) external solution revealed PPD in neonatal CA3 pyramidal neurons that was 1) partially prevented by CGP35348, 2) independent of the membrane holding potential of the recorded cell, and 3) not resulting from a change in the reversal potential of GABAA eIPSCs. In adults the GABA uptake blocker tiagabine (20 microM) increased the duration of eIPSCs and the magnitude of GABAB receptor-dependent PPD. In neonates, tiagabine also increased duration of eIPSCs but to a lesser extent than in adult and did not reveal a GABAB receptor-dependent PPD. These results demonstrate that

  12. Effects of GABA Signal on Mouse Placenta Establishment in Early-Middle Phase%γ-氨基丁酸信号对小鼠胎盘早中期建立的影响

    Institute of Scientific and Technical Information of China (English)

    罗文萍; 谭冬梅; 杨根岭; 卢俊杰; 赵海; 谭毅

    2012-01-01

    为了观察γ-氨基丁酸B型受体R1亚基(GABAB1R,GB1)在妊娠小鼠第1天至第8天(D1~D8)子宫中的表达规律,探讨γ-氨基丁酸(GABA)信号是否参与了胎盘早中期建立.应用半定量RT-PCR、免疫组织化学及Western blotting检测GB1在妊娠小鼠D1~D8子宫中的表达情况,原代分离D8.5的绒毛膜锥(EPCs)及蜕膜细胞,检测GABA及GABA B型受体激动剂baclofen、拮抗剂2-hydroxysaclofen对EPCs黏附及外延生长以及对蜕膜细胞侵袭能力的影响.D8时体内注射0.05 g/kg、0.5 g/kg及5 g/kg的GABA,于D14收集胎盘,制作石蜡切片.结果显示,GB1 mRNA及蛋白动态表达于D1~D8子宫.100 μmol/L GABA及5μmol/L Baclofen促进EPCs的外延生长,抑制蜕膜细胞的侵袭,同时,20 μmol/L 2-hydroxysaclofen 成功逆转GABA对EPCs及蜕膜细胞的侵袭调节作用.5g/kg的GABA可导致D14小鼠胎盘的迷路层滋养层细胞增多,母鼠血窦及胎鼠血管减少或发育不良,海绵滋养层的细胞滋养层细胞变小,糖原细胞减少或消失.结果提示,在小鼠早中期胎盘建立过程中,GABA信号促进滋养层侵袭至母体蜕膜组织,而抑制蜕膜细胞积极主动的侵袭行为,并可损害胎盘的结构.%To explore the expression of GB1 in mouse uterus from day 1 to day 8 of pregnancy (D1~D8) and the role in placenta establishment, semi-quantitative reverse transcription polymerase chain reaction (semi-qRT-PCR), immunohistochemistry and Western blotting were applied to detect the expression levels of GB1 mRNA and protein respectively from D1 to D8. Besides, EPCs and decidual cell were dissected out from D8.5 uterus and then added different concentrations of GABA, GABA B receptor agonists baclofen and antagonists 2-hydroxysaclofen. In vitro attachment and outgrowth assays were performed in EPCs, and transwell chambeer was performed in decidual cells. In vivo, mouse from D8 to D13 were treated by intraperitoneal injection of different concentrations of GABA . On D14

  13. 高压氧对脊髓损伤肌张力控制的队列研究%Cohort study of hyperbaric oxygention (HBO) in controlling hypermyotonia caused by spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    卢爱兰; 张夏军; 许美飞

    2012-01-01

    目的:探讨高压氧(hyperbaric oxygenation,HBO)对脊髓损伤(spinal cord injury,SCI)肌张力增高患者的治疗效果.方法:选择2009年3月至2011年4月脊髓损伤肌张力增高患者80例作为研究对象,男49例,女31例;年龄17~60岁,平均(34.12±6.61)岁;病程14~30 d,平均(20.16±5.08)d.按就诊顺序、是否愿意同时进行高压氧治疗分成治疗组和对照组.其中治疗组40例,在运动康复训练和巴氯芬药物治疗的基础上,加用HBO治疗.治疗压力为2ATA;治疗方案为:面罩吸氧20 min,休息5 min,反复3个循环为1次,每日1次,10d为1个疗程,共治疗6个疗程.对照组40例,只进行运动康复训练和巴氯芬药物治疗,疗程同治疗组.两组均按国际通用修订的Ashworth评分(modifiedashworth scale,MAS)方法分别于治疗3个疗程和6个疗程时对肌张力进行评估.结果:治疗3个疗程时对肌张力的控制,治疗组有效5例,显效0例;对照组有效4例,显效0例.治疗6个疗程时对肌张力的控制,治疗组有效24例,显效5例;对照组有效14例,显效2例.3个疗程时,治疗组与对照组疗效差异无统计学意义(P=0.508);6个疗程时治疗组疗效优于对照组(P<0.05).结论:HBO对脊髓损伤肌张力增高患者有治疗作用,可作为一种常规辅助治疗方法,在临床上值得推广应用,但需要足够的疗程.%Objective:To evaluate the clinical effects of hyperbaric oxygention (HBO) in treating hypermyotonia caused by spinal cord injury (SCI). Methods: From March 2009 to April 2011,80 patients with hypermyotonia caused by SCI were divided into treatment group and control group,with 40 cases in each group. There were 49 males and 31 females with an average age of (34.12+6.61) years (ranged, 17 to 60) in the study. Course of disease was from 14 to 30 d with an average of (20.16± 5.08) d. The patients of the treatment group were treated with HBO,rehabilitation exercise and baclofen medication. With pressure of HBO was

  14. 白香丹胶囊对愤怒情绪模型大鼠海马GABABR和KIR表达的影响%Effect of Baixiangdan Capsule on Expression of GABABR and KIR in Hippocampus of Anger-out Rat Models

    Institute of Scientific and Technical Information of China (English)

    许莉莉; 蔡洪信; 高杰; 薄蔷; 张惠云

    2012-01-01

    Objective To detect the expression of two subunits of gamma arainobutyric acid B receptor, GABABR1 andGABABR2, as well as inwardly rectifying K+ channel (KIR) in hippocampus of anger-out rat models, and to explore the intervention mechanism of Baixiangdan Capsule in teating the syndrome of adverse flow of liver-Qi. Methods The Wistar rats were divided into normal group, modle group, Baixiangdan Capsule group(ig 0.2 g·kg-1, qd, for 7 d) and baclofen group (ig 0.008 g·kg-1, qd, for 7 d). The anger-out emotion rat models were established with social isolation plus resident intruder stress. The model was evaluated by sucrose intake test, open field test and elevated plus-maze test. The expression of GABABR 1, GABABR2 and KIR in hippocampus was detected by immunofloures-cence assay. Results Compared with the normal group, the modle group had lower sucrose intake, higher total score of open field test, lower open arm entry percent(OE %) and open arm time percent(OT %) of elevated plus-maze test, and lower expression of GABABR1, GABABR2 and KIR in hippocampus(P < 0.05). Compared with the model group, Baixiangdan capsule and baclofen decreased the total score of open field test, increased OE % and OT % of elevated plus-maze test, and promoted expression of GABABR1, GABABR2 and KIR in hippocampus(P < 0.05). Conclusion The lower expression of GABABR1, GABABR2 and KIR in hippocampus may have close relationship with anger-out emotion. Increasing the expression of GABABR and the function of G protein-coupled KIR in hippocampus maybe one of the mechanism of Baixiangdan capsule in soothing liver and regulating Qi flow.%目的 检测愤怒情绪模型大鼠海马γ-氨基丁酸B受体两个亚基GABABR1、GABABR2和内向整流型钾通道( KIR)表达的变化,初步探讨白香丹胶囊对肝气逆证的中枢干预机制.方法 大鼠随机分为正常对照组、模型组、白香丹胶囊组(0.2 g·kg-1)、巴氯芬组(0.008 g·kg-1),采用“社会隔离结合居住入侵

  15. 激活GABAB受体在针刺镇痛中的作用%The Important Role of Activation of GABAB Receptors in Acupuncture Analgesia

    Institute of Scientific and Technical Information of China (English)

    朱丽霞; 叶燕燕; 莫孝荣; 吉长福

    2002-01-01

    目的:脑室注射γ-氨基丁酸(GABA)A受体的拮抗剂荷包牡丹碱(Bic)未能阻断针刺镇痛效应,微电泳导入Bic部分阻断电针抑制脊髓背角伤害性反应,说明GABA可通过激活A受体参与针刺镇痛中脊髓节段性抑制.本文进一步探讨了激活GABAB受体在针刺镇痛中的作用.方法:以辐射热照射大鼠尾部引起甩尾反射潜伏期作为痛阈的指标,以针刺"次髎"穴后痛阈最大变化百分率判断镇痛效应,观察脑室注射(icv)5 μL或蛛网膜下腔(ith)注射10μL GABAB受体的拮抗剂CGP 55845对针刺镇痛效应的影响.每组6~8例.结果:icv GABA(125 μg、250 μg、500μg)或GABAB受体激动剂苯氯丁氨酸(Baclofen,25ng、250 ng、2500 ng)可产生剂量依赖的镇痛效应.icv CGP 55845(5 ng、50 ng)可大部分阻断GABA和Baclofen的镇痛效应.针刺双侧"次髎"穴(50 Hz,1~2 mA)10 min,痛阈提高到针前值的(142.5±2.1)%,镇痛效应显著.针前icv CGP55845针后痛阈分别提高到(111.2±1.2)%和(112.1±1.1)%,阻断率分别为73.7%和71.6%,和事先icv生理盐水(143.7±2.0)%相比,阻断效应明显.若针刺前ith CGP 55845(50 ng、500ng),也能明显阻断针刺镇痛效应.结论:脑内注射GABA或Baclofen可通过激活GABAB受体产生剂量依赖的镇痛效应.在针刺镇痛效应中脑内GABA主要通过激活B受体发挥作用,而在脊髓水平激活GABAA和B受体都参与针刺镇痛效应.对GABAB受体参与针刺镇痛作用的可能机制进行了讨论.

  16. Hippocampal CA1 lacunosum-moleculare interneurons: modulation of monosynaptic GABAergic IPSCs by presynaptic GABAB receptors.

    Science.gov (United States)

    Khazipov, R; Congar, P; Ben-Ari, Y

    1995-11-01

    1. Whole cell patch-clamp recordings were employed to characterize monosynaptic inhibitory postsynaptic currents (IPSCs) in morphologically and electrophysiologically identified interneurons located in the stratum lacunosum moleculare, or near the border of the stratum radiatum (LM interneurons), in the CA1 region of hippocampal slices taken from 3- to 4-wk-old rats. Monosynaptic IPSCs, evoked in the presence of glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM) and D-2-amino-5-phosphopentanoate (APV; 50 microM) were biphasic. The gamma-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline (20 microM), blocked the fast IPSC, and the slow IPSC was blocked by the GABAB receptor antagonist CGP35348 (500 microM). 2. Monosynaptic IPSCs were evoked by electrical stimulation in several distant regions including the stratum radiatum, the stratum oriens, the stratum lacunosum-moleculare, and the molecular layer of dentate gyrus, suggesting an extensive network of inhibitory interneurons in the hippocampus. In paired recordings of CA1 interneurons and pyramidal cells, IPSCs were evoked by electrical stimulation of most of these distal regions with the exception of the molecular layer of dentate gyrus, which evoked an IPSC only in LM interneurons. 3. Frequent (> 0.1 Hz) stimulation depressed the evoked IPSCs. With a paired-pulse protocol, the second IPSC was depressed and the maximal depression (40-50%) was observed with an interstimulus interval of 100-200 ms. 4. The GABAB receptor agonist baclofen (1 microM) reduced the amplitude of evoked IPSCs and the paired-pulse depression of the second IPSC. The GABAB receptor antagonist CGP35348 (0.5-1 mM) had no significant effect on the amplitude of isolated IPSCs. However, CGP35348 reduced but did not fully block paired-pulse depression, suggesting that this depression is partly due to the activation of presynaptic GABAB receptors. 5. The paired-pulse depression depended on the level of

  17. 针药结合对脑卒中后痉挛性偏瘫的疗效观察%Efficacy Observation of Post-apoplexy Spastic Hemiplegia Treated with the Integration of Acupuncture and Medicine

    Institute of Scientific and Technical Information of China (English)

    侯震; 王瑶

    2012-01-01

    Objective To explore the efficacy on post - apoplexy spastic hemiplegia treated with the integration of acupuncture and medicine. Methods 90 cases were randomized into a treatment group( 45 cases )and a control group( 45 cases ). In the control group, the muscle relaxant, baclofen tablets were prescribed for oral administration. In the treatment group, buyang huaiwu decoction and acupuncture on the affected side were applied in combination. The treatment lasted for 2 months. Results The results of the modified Ashworth assessment did not present statistical significant differences before treatment between two groups( P >0. 05 ) indicating the comparability of two groups. After treatment,in either group,the spasm severity was alleviated as compared with that before treatment, presenting statistical significant difference( P 0. 05 ), indicating the comparability of two groups. After treatment, in either group, the motor function of the affected limbs and the daily life activity were all improved as compared with those before treatment, indicating statistical significant difference( P<0.05 ). The results in the treatment group were better than those in the control group( P <0. 05 ). Conclusion The integration of acupuncture and medicine effectively reduces the muscular tension and improves the motor function and the daily life activity.%目的 探讨针药结合治疗脑卒中后痉挛性偏瘫的疗效.方法 将90例患者随机分治疗组45例,对照组45例.对照组口服肌肉松弛剂巴氯芬片;治疗组采用补阳还五汤配合针刺患肢体的针药结合法,疗程2个月.结果 两组患者治疗前改良Ashworth评定结果比较,两组之间差异无统计学意义(P>0.05),具有可比性;两组治疗后痉挛程度均有减轻,分别与治疗前比较,差异有统计学意义(P<0.05),且治疗组优于对照组(P<0.05).两组患者治疗前患者Fugl-Mager(FMA)和Barthel(MBI)评定结果比较,差异无统计学意义(P>0.05),具有可比

  18. The clinical effects of a peony and licorice decoction combined with kinesiotherapy in the treatment of hemiplegia and elbow joint spasticity after stroke%芍药甘草汤联合运动训练治疗脑卒中偏瘫肘关节屈曲痉挛的临床分层研究

    Institute of Scientific and Technical Information of China (English)

    张颖; 高宁沁; 李擎; 范利; 葛海萍; 羊健中; 李洪丽; 袁文超; 李巍巍

    2015-01-01

    and licorice decoction combined with kinesiotherapy in treating hemiplegia and elbow joint spasticity after stroke.Methods A total of 197 patients suffering from hemiplegia complicated with elbow joint flexion spasticity after stroke were classified into different levels according to the severity of the spasticity.Patients of different levels were divided into a treatment group (receiving peony and licorice decoction combined with kinesiotherapy),a control group 1 (receiving kinesiotherapy solely) and a control group 2 (accepting baclofen and kinesiotherapy).Before and after 3 weeks of treatment,the 3 groups were evaluated by using the modified Ashworth scale (MAS),the modified Barthel index (BI),the Fugl-Meyer assessment (FMA) and the Berg Balance Scale (BBS).Results The spasticity of patients with spasticity at level Ⅰ in the treatment group and control group 2 demonstrated significantly greater relief compared with those in control group 1.The BI,FMA and BBS scores of the treatment group were significantly better than those of both control groups.Among the patients with level Ⅰ + spasticity,the spasticity,BI and FMA scores of the treatment group and the control group 2 were all significantly better on average than those in control group 1.The BBS score of the treatment group was significantly higher than that of either control group.For patients with level Ⅱ spasticity the average BBS score of control group 2 was significantly better than that of control group 1,but no significant difference was observed between the treatment group and control group 1.The BI and FMA scores of control group 2 were,however,significantly more improved than those of the treatment group and control group 1.Conclusion Peony and licorice decoction combined with kinesiotherapy is applicable to patients with mild spasticity complicating hemiplegia after stroke.It not only can relieve spasticity,but also improves upper limb motor function,ability in the activities of daily living and

  19. Effects of gamma-aminobutyric acid type B receptors on hippocampus of rats with paclitaxol-induced neuropathic pain and the relationship with nuclear factor-κB pathway%γ-氨基丁酸B型受体对紫杉醇诱发神经痛大鼠海马核因子-κB通路的影响

    Institute of Scientific and Technical Information of China (English)

    李昭; 赵爽; 王秀丽; 刘飞飞; 杨淑红; 石娜; 郭跃先

    2016-01-01

    .04;D3组:1.08±0.06;D4组:0.88±0.09)及TNF-α蛋白(D2组:0.98±0.07;D3组:1.00±0.04;D4组:0.71 ±0.08)表达下降(P<0.05).结论 紫杉醇可下调大鼠海马GABAB1受体、上调NF-κB及下游炎性因子IL-1β、TNF-α蛋白表达,诱发神经痛;激活GABAB受体可协同提高NF-κB通路抑制剂作用,改善大鼠疼痛状态.NF-κB在其中发挥关键作用.%Objective To evaluate the effects of gamma-aminobutyric acid type B (GABAB) receptors on hippocampus of rats with paclitaxol-induced neuropathic pain and the relationship with nuclear factor-kappa B (NF-κB) pathway by using GABAB receptor agonist (baclofen) and the NF-κB inhibitor (SN50).Methods Pathogen-free male Sprague-Dawley rats,weighing 160-180 g,were used in this study.All the 50 rats were randomly divided into two groups:normal control group (C group,n =10)and paclitaxol-induced neuropathic pain model group (n =40),which was given intraperitonealy saline or paclitaxol respectively.The rat paclitaxol-induced neuropathic pain model was establishing by intraperitoneal injection.Mechanical paw withdrawal threshold (MWT) was used to confirm the successful establishment of the models at 2nd week after the first administration of paclitaxol (T1).Forty paclitaxol-induced neuropathic pain model rats were randomly divided into 4 groups (n =10 each):saline 10 μl + saline 10 μl were injected intrathecally in D1 group;saline 10 μl + baclofen 0.5 μg in D2 group;saline 10 μl + SN50 200 ng in D3 group;SN50 200 ng + baclofen 0.5 μg in D4 group;saline 10 μl + saline 10 μl were injected intrathecally in l0 normal rats (C group).There was an interval of 15 min between twice intrathecal injections in five groups.The MWT was measured before (T2) and 120 min (T3) after intrathecal in jection respectively.At the end of behavior test,the hippocampi of rats were removed for detection of GABAB1 receptor,NF-κB and inflammatory factors [interleukin (IL)-1β,tumor necrosis factor-α(TNF-α)] expression using

  20. Secondary spasmodic torticollis and balance in hemiplegic stroke patients%痉挛性斜颈对脑卒中偏瘫患者平衡功能的影响及其治疗效果观察

    Institute of Scientific and Technical Information of China (English)

    郭钢花; 王国胜; 李哲

    2013-01-01

    Objective To observe the influence of secondary spasmodic torticollis on the balance of hemiplegic stroke survivors and to compare the effects of different treatment protocols.Methods Fifty-six secondary spasmodic torticollis patients after stroke were randomly divided into three groups based on the type of treatment.The botulinum toxin (BTX) group received BTX-A injections and common support treatment plus rehabilitation training (n =19),the medication therapy group received oral baclofen and common support treatment plus rehabilitation training (n =18),and the routine rehabilitation group received only routine rehabilitation therapy (n =19).In addition,19 stroke cases without spasmodic torticollis served as a control group.They also were treated with routine rehabilitative treatment alone.Before and after 2 months of treatment,balance was assessed using Berg's balance scale,and spasmodic torticollis was evaluated using Tsui's scale.Results Before treatment the balance of the control group members was significantly better than that of the other three groups.After 2 months of therapy,balance function had improved significantly in all four groups.The balance of the botulinum toxin group was better than that of the medication and routine rehabilitation groups.After treatment,Tsui scale scores in the medication and botulinum toxin groups were significantly lower than before treatment,and the scores in the botulinum toxin group were significantly lower than in the medication and routine rehabilitation groups.There was no significant difference in Tsui scale scores before and after treatment in the control group.Conclusions Spasmodic torticollis inflaences the recovery of balance function in hemiplegic patients after stroke.Treating the spasmodic torticollis can improve their balance.Treatment with BTX-A combined with common support treatmcnt and rehabilitation training showed significant curativeeffect.%目的 观察继发痉挛性斜颈对脑卒中偏瘫患者平衡

  1. Selective lumbosacral posterior and anterior rhizotomy for mixed cerebral palsy%选择性腰骶脊神经后根+前根切断术治疗混合型脑瘫

    Institute of Scientific and Technical Information of China (English)

    王逢贤; 徐林; 曹旭; 俞兴; 穆晓红; 吴坤懂

    2012-01-01

    Objectives: To investigate the efficacy of selective posterior rhizotomy(SPR) with selective anterior rhizotomy (SAR) for the treatment of mixed cerebral palsy. Methods: 48 patients with an average age of 8.8 years old(3-22 years) were reviewed retrospectively from January 2004 to January 2010. There were 36 males and 12 females. All cases had mixed cerebral palsy, and all patients presented with spasm compliacted with lower limb athetosis, the muscular tension according to Ashworth spasticity scale was grade 3. Preopera-tive lower limb dysfunction included: walking independently in 36 cases, walking with assistance in 8 cases and standing with assistance in 4 cases. SPR with SAR was applied in all cases. The L5 and SI posterior roots in 38 cases and L4, L5 and SI posterior roots in 10 cases were cut off partly in accordance with the degree of lower limb spasticity by preoperativc physical exam. 30-50 percent of the posterior nerve roots were cut off. The L5 anterior roots in 28 cases and S1 anterior roots in 20 cases were cut off partly in accordance with the degree of athetosis. 30 percent of the anterior nerve roots were cut off. Laminae were maintained as far as possible so as not to violate the stability of spine. Results: Postoperative leg or foot numbness were noted in 2 cases, lower limb weakness in 3 cases, low back pain in 2 cases, lower back weakness in 5 cases, urine dysfunction in 1 case, all these were resolved by the corresponding intervention in six months. The average follow-up was 18 months, 48 cases with muscle tension at 1 week, 6 months, 18 months after operation improved significantly compared with preopeiation, and the spasm relief rate reached 100%. As for the lower limb athctosis: after 1 week, deterioration was noted in 1 case, which was controlled satisfactively after administration of sedative drugs and baclofen; unchanged in 4, and excellent in 43 cases; after 6 months, unchanged in 5 cases and excellent in 43 cases, no case was noted