RESUMO
Previous studies from our laboratory have shown sex differences in the behavioral, molecular, and neurochemical manifestations of morphine withdrawal and they were related to an increased sensitivity to morphine effects in males. In addition, we observed an interaction between the GABAergic and opioid systems that could also be sex-dependent. Baclofen, a GABAB receptor agonist, prevented the somatic expression and the molecular and neurochemical changes induced by morphine withdrawal syndrome in mice. On the contrary, little is known about baclofen effects in the rewarding properties of morphine in male and female mice. The present study aimed to explore the effect of baclofen (1, 2 and 3 mg/kg, i.p.) pretreatment in the rewarding effects induced by morphine (7 mg/kg, s.c.) and its effect on c-Fos and brain-derived neurotrophic factor (BDNF) expression induced by the rewarding properties of morphine in prepubertal male and female mice. Baclofen (2 mg/kg) pretreatment prevented the rewarding effects of morphine only in male mice, while baclofen (3 mg/kg) reduced these effects in both sexes. Moreover, the rewarding effects of morphine were associated with a decrease of BDNF and c-Fos expression cingulate cortex, nucleus accumbens shell, cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) areas of the hippocampus only in male mice. In addition, baclofen pretreatment prevented these changes in BDNF, but not in c-Fos expression. In conclusion, our results show that GABAB receptors have a regulatory role in the rewarding effects of morphine that could be of interest for a potential future therapeutic application in opioid use disorders.
Assuntos
Baclofeno , Fator Neurotrófico Derivado do Encéfalo , Morfina , Proteínas Proto-Oncogênicas c-fos , Recompensa , Animais , Baclofeno/farmacologia , Masculino , Feminino , Morfina/farmacologia , Camundongos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Agonistas dos Receptores de GABA-B/farmacologia , Caracteres Sexuais , Comportamento Animal/efeitos dos fármacos , Fatores SexuaisRESUMO
The evolution of neurosurgical approaches to spasticity spans centuries, marked by key milestones and innovative practitioners. Probable ancient descriptions of spasmodic conditions were first classified as spasticity in the 19th century through the interventions of Dr. William John Little on patients with cerebral palsy. The late 19th century witnessed pioneering efforts by surgeons such as Dr. Charles Loomis Dana, who explored neurotomies, and Dr. Charles Sherrington, who proposed dorsal rhizotomy to address spasticity. Dorsal rhizotomy rose to prominence under the expertise of Dr. Otfrid Foerster but saw a decline in the 1920s due to emerging alternative procedures and associated complications. The mid-20th century saw a shift toward myelotomy but the revival of dorsal rhizotomy under Dr. Claude Gros' selective approach and Dr. Marc Sindou's dorsal root entry zone (DREZ) lesioning. In the late 1970s, Dr. Victor Fasano introduced functional dorsal rhizotomy, incorporating electrophysiological evaluations. Dr. Warwick Peacock and Dr. Leila Arens further modified selective dorsal rhizotomy, focusing on approaches at the cauda equina level. Later, baclofen delivered intrathecally via an implanted programmable pump emerged as a promising alternative around the late 1980s, pioneered by Richard Penn and Jeffrey Kroin and then led by A. Leland Albright. Moreover, intraventricular baclofen has also been tried in this matter. The evolution of these neurosurgical interventions highlights the dynamic nature of medical progress, with each era building upon and refining the work of significant individuals, ultimately contributing to successful outcomes in the management of spasticity.
Assuntos
Espasticidade Muscular , Rizotomia , Rizotomia/história , Rizotomia/métodos , Espasticidade Muscular/cirurgia , Humanos , História do Século XX , História do Século XIX , História do Século XXI , Procedimentos Neurocirúrgicos/história , Procedimentos Neurocirúrgicos/métodos , Baclofeno/uso terapêutico , Baclofeno/história , Paralisia Cerebral/cirurgia , Paralisia Cerebral/história , História do Século XVIIIRESUMO
Limited therapies are available for severe cerebral palsy children (CP) with complex movement disorders, especially when both dystonia and spasticity are present. In this publication, we present the improvement of a child with severe CP after intracerebroventricular baclofen therapy. The treatment can impact not just the movement disorders but also on the quality of life of the child and caregivers. Global functional improvements can be observed on the 6-month follow-up.
Assuntos
Paralisia Cerebral , Transtornos dos Movimentos , Relaxantes Musculares Centrais , Criança , Humanos , Baclofeno , Paralisia Cerebral/complicações , Paralisia Cerebral/tratamento farmacológico , Qualidade de Vida , Bombas de Infusão Implantáveis , Espasticidade Muscular/tratamento farmacológicoRESUMO
Previous studies have demonstrated the role of γ-aminobutyric acid type B (GABAB) receptors in skin-related conditions and pain. However, most studies have focused on the main effects of GABAB on the central nervous system. Therefore, this study has aimed to determine the potential topical anti-inflammatory and anti-proliferative effects of baclofen cream in an inflammatory skin disease model. The effects of the baclofen cream were evaluated using acute and chronic models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mouse ears. Histological and immunohistochemical evaluations were performed using an ear oedema assay. The effect of baclofen on keratinocyte proliferation was assessed in PAM212, the murine keratinocyte cell line. The results demonstrate that a single topical application of 5% baclofen, 7.5% baclofen, and 1% dexamethasone each inhibited acute TPA-induced ear oedema (58.94 ± 6.14%, 47.73 ± 11.26%, and 87.33 ± 4.59%, respectively). These results were confirmed by histological analysis. In the chronic model, baclofen (5%) and dexamethasone (1%) each inhibited ear oedema and the maximum inhibitory effect was reached at the end of the experiment (9th day of TPA application) with a percentage inhibition of 54.60 ± 6.15% for baclofen and 71.68 ± 3.45% for dexamethasone, when compared to the vehicle. These results were confirmed by histological analysis. Baclofen and dexamethasone also reduced proliferating cell nuclear antigen expression by 62.01 ± 6.65% and 70.42 ± 6.11%, respectively. However, baclofen did not inhibit keratinocyte proliferation in PAM212 cells. In conclusion, these results demonstrate that baclofen exhibits notable topical antiproliferative and anti-inflammatory properties and could be a potential therapeutic alternative for treating inflammatory and proliferative skin diseases.
Assuntos
Dermatite , Dermatopatias , Animais , Camundongos , Baclofeno/farmacologia , Baclofeno/uso terapêutico , Agonistas dos Receptores de GABA-B/farmacologia , Agonistas dos Receptores de GABA-B/uso terapêutico , Dermatopatias/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Inflamação/tratamento farmacológico , Dexametasona/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Acetato de Tetradecanoilforbol/uso terapêuticoRESUMO
The absence of oral liquid pharmaceutical forms appropriate for use in pediatric and adult patients with difficulty swallowing is a public health problem, especially in the hospital context. Baclofen is a muscle relaxant of choice for treating spasticity, generally marketed only in tablet form, highlighting the need for liquid formulations to facilitate dose adjustment, administration, and swallowing. The present study aimed to develop oral liquid formulations containing baclofen, optimize them through the quality by design approach, and evaluate their physicochemical and microbiological stability. Preformulation and preliminary stability studies were carried out for the development of formulations. Experimental screening and optimization designs resulted in eleven experiments for each step that were evaluated for 28 days. A stability-indicating method by high-performance liquid chromatography presented linearity, low limits of detection and quantification, precision, accuracy, and robustness. The experimental design led to two optimized formulations containing baclofen, glycerin, potassium sorbate, citric acid, ultrapure water, flavor, and sucrose syrup or sodium carboxymethylcellulose solution as a vehicle, the last one with sucralose as a sweetener. The formulations were placed in amber glass flasks and subjected to a physicochemical and microbiological stability study. Both formulations showed physicochemical and microbiological stability when stored at room temperature and refrigerated for 84 days. The results of this study may serve as a reference in the preparation of liquid oral formulations containing baclofen in the hospital routine and collaborate with the safety and adherence to the treatment of adult and pediatric patients.
Assuntos
Baclofeno , Excipientes , Humanos , Criança , Estabilidade de Medicamentos , Composição de Medicamentos , Comprimidos , Excipientes/química , HospitaisRESUMO
Baclofen was approved for medical use in the United States in 1977 by Food and Drug Administration. Serious adverse effects associated with this medication are uncommon at usually prescribed doses. Herein, we present a case of baclofen-induced catatonia in a young-adult female with back pain receiving oral baclofen. A 20-year-old female presented to the emergency department with possible seizure-like activity. It was reported that the patient was suffering from acute back pain and was prescribed baclofen three times a day by her general physician one day before her presentation. Upon further discussion, it was known that following an altercation with her family member, she had attempted suicide by consuming 200 mg of baclofen and then developed rapidly progressive symptoms of aphasia, mutism, and decreased oral intake. Laboratory tests, cerebrospinal fluid analysis, and neuroimaging were unremarkable. Electroencephalogram was normal. Bush-Francis Catatonia Rating Scale score was 27. She showed significant improvement following low-dose lorazepam administration. There are four reports in the literature of catatonia secondary to baclofen. The present report is the first to describe the occurrence of catatonia in a previously healthy individual. Analysis of these cases suggests a relationship between a history of psychotic symptoms and catatonia. All the reports were classified as probable by the Naranjo algorithm.
Assuntos
Catatonia , Transtornos Psicóticos , Humanos , Adulto , Feminino , Adulto Jovem , Catatonia/induzido quimicamente , Catatonia/diagnóstico , Catatonia/tratamento farmacológico , Baclofeno/efeitos adversos , Lorazepam , Transtornos Psicóticos/tratamento farmacológicoRESUMO
PURPOSE: This study aims to describe a new baclofen pump implantation technique with pre-brainstem catheter placement and to demonstrate the benefits that this procedure has in treating spasticity and dystonia. METHODS: We described a new technique to place a baclofen pump catheter anterior to the brainstem. To illustrate the technique, we presented five patients with both spasticity and dystonia in whom conventional treatment was not effective. They each received a baclofen pump with a pre-brainstem catheter. We evaluated the results using the Ashworth scale for spasticity, the Barry-Albright scale for dystonia, and the PedsQL for quality of life assessment. Each patient was evaluated before a surgery and after 6 months of follow-up. RESULTS: There were statistically significant differences in all the physical examination evaluated areas using the Barry-Albright and modified Ashworth scales between the preoperative and the postoperative period. The same applies to the results of the PedsQL quality of life scale. CONCLUSION: We presented an innovative baclofen pump implantation technique with pre-brainstem catheter placement that could be a therapeutic alternative in patients with dystonia and spastic quadriparesis for whom conventional therapy is not effective.
Assuntos
Paralisia Cerebral , Relaxantes Musculares Centrais , Baclofeno , Tronco Encefálico , Paralisia Cerebral/complicações , Paralisia Cerebral/tratamento farmacológico , Humanos , Bombas de Infusão Implantáveis , Espasticidade Muscular/tratamento farmacológico , Qualidade de VidaRESUMO
There are many medications available to treat spasticity, but the tolerability of medications is the main issue for choosing the best treatment. The objectives of this study were to compare the efficacy and adverse effects of tolperisone compared to baclofen among patients with spasticity associated with spinal cord injury. Patients received baclofen plus physical therapy (BAF+PT, n=135) or tolperisone plus physical therapy (TOL+PT, n=116), or physical therapy alone (PT, n=180). The modified Ashworth scale score, the modified Medical Research Council score, the Barthel Index score, and the Disability Assessment scale score were improved (P<0.05 for all) in all the patients at the end of 6 weeks compared to before interventions. After 6 weeks, the overall coefficient of efficacy of the intervention(s) in the BAF+PT, TOL+PT, and PT groups were 1.15, 0.45, and 0.05, respectively. The patients of the BAF+PT group reported asthenia, drowsiness, and sleepiness and those of the TOL+PT group reported dyspepsia and epigastric pain as adverse effects. When comparing drug interventions to physical therapy alone, both baclofen plus physical therapy and tolperisone plus physical therapy played a significant role in the improvement of daily activities of patients. Nonetheless, baclofen plus physical therapy was tentatively effective. Tolperisone plus physical therapy was slightly effective. In addition, baclofen caused adverse effects related to the sedative manifestation (Level of Evidence: III; Technical Efficacy Stage: 4).
Assuntos
Humanos , Traumatismos da Medula Espinal/complicações , Tolperisona , Relaxantes Musculares Centrais/efeitos adversos , Baclofeno/efeitos adversos , China , Estudos RetrospectivosRESUMO
Purpose of Review: This review will cover seminal and emerging evidence on interventional therapy chronic pain in cerebral palsy (CP). It will cover the background and burden of disease, present the current options, and then weigh the evidence that is available to support interventional therapy and the current indications. Recent Findings: CP is a permanent posture and movement disorder from in-utero brain development defects with a 3-4/1,000 incidence in the US. The cost of care for each child is estimated at $921,000. Pain in CP is attributed to musculoskeletal deformities, spasticity, increased muscle tone, dislocations, and GI dysfunction. First-line treatments include physical and occupational therapy and oral pharmacological agents; however, a significant amount of patients remain refractory to these and require further therapy. Injection therapy includes botulinum toxin A (BTA) injections and intrathecal baclofen. BTA injections were shown to control chronic pain effectively and are FDA approved for spastic pain; intra-thecal baclofen, in contrast, was only shown to improve comfort and quality of life with a focus on the pain. Surgical intervention includes selection dorsal rhizotomy (SDR). It may increase range of motion and quality of life and reduce spasticity and pain; however, most evidence is anecdotal, and more research is required. Summary: Interventional therapy, including injection and surgical, is the last line of therapy for chronic pain in CP. It extends the possibility of therapy in hard-to-treat individuals; however, more data is required to provide strong evidence to the efficacy of these treatments and guide proper patient selection.
Assuntos
Paralisia Cerebral , Espasticidade Muscular , Paralisia Cerebral/complicações , Paralisia Cerebral/cirurgia , Criança , Humanos , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/etiologia , Dor , Qualidade de Vida , RizotomiaRESUMO
GABAB and 5-HT2C agonists are effective in attenuating the behavioral effects of psychostimulants. However, they induce adverse side effects when used in high doses. The previous evidence has suggested that the 5HT2C receptor activation effect could be produced by an increased release of GABA in the ventral tegmental area (VTA) and the consequent activation of GABAergic receptors. Therefore, the objective of this study was to evaluate the effects of joint administration of an intermediate dose of the GABAB agonist baclofen (3.0 mg/kg) with different doses of the 5HT2C agonist Ro60-0175 (0.3, 1.0, and 3.0 mg/kg) on the locomotor sensitization expression induced by the repeated administration of amphetamine (1.0 mg/kg). Our results showed an attenuation of the expression of sensitization in a dose-dependent manner with both agonists. In both cases, we observed a complete blockade at the highest dose. In addition, the intermediate dose of baclofen increased the effects of the three doses of Ro60-0175. These results support the role of the joint action of GABAB and 5-HT2C receptors in the effects of psychostimulants. However, it remains to be explored whether the observed effect can be attributed to receptors located in the VTA or the nucleus accumbens.
Assuntos
Anfetamina/administração & dosagem , Baclofeno/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Agonistas dos Receptores de GABA-B/administração & dosagem , Atividade Motora/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Masculino , Atividade Motora/fisiologia , Ratos , Ratos WistarRESUMO
El baclofeno es un análogo estructural del ácido gamma-aminobutÃrico empleado principalmente como relajante del músculo esquelético para el tratamiento de espasticidad y distonÃas. Las manifestaciones clÃnicas de intoxicación por este fármaco, se deben a alteración del nivel de conciencia que produce somnolencia, estado de coma e incluso la muerte. Desde el punto de vista electroencefalográfico, se ha descrito en estos casos, el llamado patrón de brote- supresión. Se presenta el caso de una mujer que súbitamente presentó dificultad para la bipedestación y mutismo acinético y, posteriormente, evolucionó a un estado de coma sin causa aparente. Una evaluación minuciosa en el Servicio de Emergencia, incluyó electroencefalograma urgente que resultó compatible con un patrón continuo de brote-supresión. Ante la sospecha de una intoxicación por baclofeno, la paciente fue tratada con diálisis, la cual revirtió el cuadro clÃnico y normalizó la actividad electroencefalográfica en un periodo de cinco dÃas.
Baclofen is a structural analog of gamma-aminobutyric acid, primarily used as a skeletal muscle relaxant for treatment of spasticity and dystonia. The clinical picture of baclofen intoxication includes reduction or loss of consciousness and manifestations such as sleepness, coma or even death. Electroencephalograms performed in these cases have consistently shown the so-called burst-suppression pattern. The case of a female patient who suddenly presented difficulty to still-standing and mutism and later evolved into coma, is presented. A detailed study was performed in the emergency department, including an electroencephalogram compatible with a continuous burst-suppression pattern. The patient was treated with dialysis in the face of a possible baclofen intoxication and, in a period of five days, the clinical symptoms reverted and the electroencephalographic activity was normalized.
RESUMO
Previous studies in our laboratory showed an interaction between the GABAergic and opioid systems involved in the analgesic effect of baclofen (BAC). Furthermore, it is known that sex differences exist regarding various pharmacological responses of morphine (MOR) and they are related to an increased sensitivity to MOR effects in males. The aims of the present study were to evaluate the possible involvement of the GABAB receptors in the antinociceptive responses induced by MOR (1, 3 and 9â¯mg/kg, s.c.) administration using both pharmacological (BAC 2â¯mg/kg, i.p.; and 2-OH-saclofen, SAC 0.3â¯mg/kg, intra cisterna magna) and genetic approaches (GABAB1 knockout mice; GABAB1 KO) in mice of both sexes. In addition, we explored the alterations in c-Fos expression of different brain areas involved in the antinociceptive effect of MOR using both approaches. The pharmacological approach showed a higher dose-dependent antinociceptive effect of MOR in male mice compared to female mice. BAC and SAC pretreatment potentiated and attenuated the antinociceptive effect of MOR, respectively, in both sexes. The genetic approach revealed a dose-dependent antinociceptive effect of MOR in the wild type mice, but not in the GABAB1 KO mice and no sex differences were observed. Additionally, BAC and SAC pretreatment and the lack of GABAB1 subunit of the GABAB receptor prevented the changes observed in c-Fos expression in the cingulate cortex and nucleus accumbens of male mice. Our results suggest that the GABAB receptors are involved in the MOR antinociceptive effect of both male and female mice.
Assuntos
Analgésicos/farmacologia , Morfina/farmacologia , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Analgésicos/administração & dosagem , Animais , Baclofeno/administração & dosagem , Baclofeno/análogos & derivados , Baclofeno/farmacologia , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Agonistas dos Receptores de GABA-B/administração & dosagem , Agonistas dos Receptores de GABA-B/farmacologia , Técnicas de Inativação de Genes , Genes fos/genética , Genótipo , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Morfina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-fos/imunologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacosRESUMO
The endocrine disruptor di-(2-ethylhexyl) phthalate (DEHP) is used in a variety of consumer products made with polyvinyl chloride and also in the manufacture of medical devices. DEHP disrupts reproductive tract development in an antiandrogenic manner and also may induce neurobehavioral changes. The aim of this study was to investigate the effects of chronic postnatal exposure to DEHP (30 mg/kg body weight/day, orally from birth to day 60) on the neuroendocrine regulation of the gonadal axis and its impact on the anxiety-like behavior in adult male rats, as well as the probable participation of the GABAergic system in these effects. DEHP produced a significant increase in plasmatic luteinizing hormone and follicle stimulating hormone, as well as significant testosterone decrease, accompanied with a decrease in hypothalamic gamma-aminobutyric acid (GABA) concentration. On the other hand, DEHP increased the anxiety-like behavior in the elevated plus maze test, evidenced by a significant decrease in the percentages of time spent in the open arms and the frequency in the open arm entries and a significant increase in the percentage of time spent in closed arms. Neuroendocrine and behavioral effects were reversed by GABA agonists, muscimol (2 mg/kg i.p. ) and baclofen (10 mg/kg i.p.). In conclusion, chronic DEHP postnatal exposure induced a disruption in the neuroendocrine regulation of the testicular axis in young adult male rats, and this effect was correlated with an anxiety-like behavior. Since GABA agonists reversed these effects, the results suggest that GABA could participate in the modulation of reproductive and behavioral DEHP effects.
Assuntos
Ansiedade/metabolismo , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Ácido gama-Aminobutírico/metabolismo , Animais , Animais Recém-Nascidos , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Feminino , Hormônio Foliculoestimulante/sangue , Agonistas de Receptores de GABA-A/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hormônio Luteinizante/sangue , Masculino , Ratos Wistar , Reprodução/efeitos dos fármacos , Testosterona/sangueRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Piper auritum Kunth is employed as an aphrodisiac in the traditional medicine, but corroborative evidence for such effect is scarce. AIM OF THE STUDY: The pro-sexual effect of an aqueous extract of P. auritum and its possible mechanisms were analyzed in two paradigms of male sexual function. MATERIAL AND METHODS: Effects of an aqueous extract of P. auritum (PA, single administration) were investigated in the fictive ejaculation, and copulatory behavior paradigms in sexually sluggish male rats. WAY 100635 (antagonist of 5-HT1A receptors), atosiban (antagonist of oxytocinergic receptors), L-NAME (inhibitor of the nitric oxide synthase) and baclofen (antagonist of GABAB receptors) were used as pre-treatments in order to investigate the role of different neurotransmitter systems in PA actions. Chemical profile of PA was determined by Gases Chromatography and Ultra Performance Chromatography-Electrospray Ionization-Masses Spectrometry (UPLC-ESI-MS). RESULTS: In males with retarded ejaculation, PA stimulated ejaculatory behavior and recovered electromyographic activity of pelvic musculature participating in seminal emission and ejaculation. All pre-treatments blocked stimulating effects of PA on the fictive ejaculation; additionally WAY 100635 interfered with PA actions on ejaculatory behavior. Safrol, apigenin dimethylether, myristicin, vaccihein A, sakuranin and sakuranetin flavonoids, were main constituents of PA, with possible participation in its pro-sexual effects. CONCLUSIONS: Pro-sexual effects of P. auritum elicited at level of ejaculation were mediated by several neurotransmitter systems, among which serotonin and its 5-HT1A receptors play an important role. Present findings support P. auritum reputation as an aphrodisiac, with potential use in delayed ejaculation disorder.
Assuntos
Afrodisíacos/farmacologia , Piper , Extratos Vegetais/farmacologia , Comportamento Sexual/efeitos dos fármacos , Animais , Afrodisíacos/química , Comportamento Animal/efeitos dos fármacos , Ejaculação/efeitos dos fármacos , Feminino , Masculino , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Piper/química , Piperazinas/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Piridinas/farmacologia , Ratos Wistar , Receptor 5-HT1A de Serotonina/fisiologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
The mechanisms commanding the activity of dopaminergic neurons of the ventral tegmental area (VTA) and the location of these neurons are relevant for the coding and expression of motivated behavior associated to reward-related signals. Anatomical evidence shows that several brain regions modulate VTA dopaminergic neurons activity via multiple mechanisms. However, there is still scarce knowledge of how the lateral septum (LS) modulates VTA activity. We performed in-vivo dual-probe microdialysis to measure VTA dopamine, glutamate and GABA extracellular levels after LS stimulation in the presence or absence of GABAergic antagonists. Anterograde tracing and immunohistochemical analysis was used to reveal the anatomical relationship between LS and VTA. LS stimulation significantly increased dopamine and GABA, but not glutamate, VTA extracellular levels. Intra VTA infusion of bicuculline, GABA-A receptor antagonist, inhibited the increase of dopamine but not of GABA VTA levels induced by LS stimulation. Intra VTA infusion of indiplon, selective positive allosteric modulator of GABA-A receptors containing alpha1 subunit, significantly increases VTA dopamine extracellular levels induced by LS. Combined c-Fos and tyrosine hydroxylase immunohistochemistry, revealed that LS stimulation increases the activity of dopaminergic neurons in the antero-ventral region of the VTA. Consistently, anterograde tracing with biotinylated dextran amine revealed the existence of fibers arising from the LS to the antero-ventral region of the VTA. Taken together, our results suggest that LS modulates dopaminergic activity in the antero-ventral region of VTA by inhibiting GABAergic interneurons bearing GABA-A receptors containing alpha1 subunit.
Assuntos
Neurônios Dopaminérgicos/fisiologia , Vias Neurais/fisiologia , Receptores de GABA-A/metabolismo , Núcleos Septais/fisiologia , Área Tegmentar Ventral/citologia , Análise de Variância , Animais , Benzilaminas/farmacologia , Biotina/análogos & derivados , Biotina/metabolismo , Dextranos/metabolismo , Dopamina/metabolismo , Relação Dose-Resposta a Droga , GABAérgicos/farmacologia , Ácido Glutâmico/metabolismo , Masculino , Ácidos Fosfínicos/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Para el manejo médico de la distonía se han utilizado tradicionalmente varios fármacos encaminados a disminuir esta condición y a mejorar la calidad de vida. Las terapias orales solas o combinadas proporcionan control parcial de los síntomas y en la mayoría de los casos hay que recurrir a terapias invasivas.
SUMMARY During the last years, several drugs has been tried in order to try to diminish the impact of this condition and improve the quality of life of patients who suffer from dystonia. Oral therapy alone or in combination, generates only partial symptom relief and most of the cases end up requiring other more invasive therapies.
Assuntos
Baclofeno , Antagonistas Colinérgicos , DistoniaRESUMO
RESUMEN Para el manejo médico de la distonía se han utilizado tradicionalmente varios fármacos encaminados a disminuir esta condición y a mejorar la calidad de vida. Las terapias orales solas o combinadas proporcionan control parcial de los síntomas y en la mayoría de los casos hay que recurrir a terapias invasivas.
SUMMARY During the last years, several drugs has been tried in order to try to diminish the impact of this condition and improve the quality of life of patients who suffer from dystonia. Oral therapy alone or in combination, generates only partial symptom relief and most of the cases end up requiring other more invasive therapies.
Assuntos
Baclofeno , Antagonistas Colinérgicos , DistoniaRESUMO
RESUMEN Existen enfermedades y condiciones que se presentan con movimientos involuntarios hipercinéticos de aparición súbita y remisión espontanea (episódicas). Dichas condiciones generan dificultades diagnósticas ya que por su carácter intermitente, en ocasiones no pueden ser evaluadas por el clínico.
SUMMARY During the last years, several drugs has been tried to try to diminish the impact of this condition and improve quality of life the people who suffer from dystonia. Oral therapy alone or in combination generates only partial symptom relief and most of the cases end up requiring other more invasive therapies.
Assuntos
Distonia Paroxística Noturna , Diagnóstico Diferencial , DistoniaRESUMO
Introducción: el baclofeno se indica como relajante muscular para el alivio de espasticidad grave y ejerce sus efectos como agonista selectivo del receptor GABA-B. Objetivo: caracterizar las intoxicaciones por baclofeno según reportes al Servicio de Información de Urgencia del Cenatox entre 2011 y 2015. Métodos: se realizó un estudio observacional retrospectivo con un universo de 16 notificaciones, en las que se estudiaron: el centro de salud que asistió al paciente, provincia de procedencia por año de estudio, grupo de edad, sexo, circunstancias del evento, manifestaciones clínicas y severidad de la intoxicación. Resultados: el año 2014 aportó la mayor cantidad de reportes y los niños las mayores frecuencias absolutas, no hubo diferencias en relación al sexo, aunque entre los hombres predominó la causa accidental y entre las féminas las intencionales suicidas. Todas las notificaciones procedieron de atención secundaria, aunque cinco de los pacientes habían sido previamente asistidos en áreas de salud. Todos los afectados presentaron manifestaciones neurológicas, la mayoría fueron reportados de grave y la mitad de los casos presentaron alteraciones cardiorrespiratorias con inestabilidad hemodinámica que llevó a la asistencia ventilatoria. La recuperación fue completa en todos los pacientes y no se reportaron fallecidos por esta causa durante el período de estudio. Conclusiones: la sobredosis de baclofeno es más común en niños y cursa con manifestaciones de neurotoxicidad e inestabilidad hemodinámica(AU)
Introduction: Baclofen is indicated as a muscle relaxant for the relief of severe spasticity and exerts its effects as a selective agonist of the GABA-B receptor. Objective: To characterize baclofen poisonings according to reports to the Cenatox emergency information service between 2011 and 2015. Methods: A retrospective observational study with a universe of 16 notifications, in which the health center that attended the patient and province of origin was studied by year of study, age group, gender, circumstances, clinical manifestations and severity of intoxication. Results: The bigger number of reports and the highest absolute frequencies occurred in the year 2014, there were no differences with regard to sex, although among the men, the accidental cause was predominant, and among women the suicides attemps were predominant. All reports came from secondary care, although five of the patients had previously been assisted in health care areas; all affected had neurological manifestations, most were reported as severe and half of the cases presented cardiorespiratory alterations with hemodynamic instability leading to ventilatory assistance. Recovery was complete in all patients and no deaths were reported for this cause during the study period. Conclusions: Baclofen overdose was more common in children and was characterized by neurotoxicity and hemodynamic instability(AU)
Assuntos
Humanos , Masculino , Feminino , Intoxicação/complicações , Baclofeno/administração & dosagem , Síndromes Neurotóxicas/terapia , Estudos Retrospectivos , Estudo ObservacionalRESUMO
La espasticidad puede causar inmovilidad, postración, dolor crónico, úlceras, infecciones, trombosis y neumonías; los objetivos del tratamiento son controlar el dolor, mejorar la movilidad y la calidad de vida y reincorporar al paciente a sus actividades cotidianas por medio de medicamentos antiespásticos orales; sin embargo, los pacientes con espasticidad severa pueden requerir altas dosis orales de estos medicamentos y presentar efectos adversos, por lo que se ha planteado el uso del baclofeno por vía intratecal; en Colombia no se ha usado ampliamente esta intervención y no existen protocolos sobre las indicaciones para llevarla a cabo. El objetivo de esta serie de casos es presentar la experiencia de la Fundación Cardiovascular de Colombia en el tratamiento con bombas intratecales de baclofeno de cuatro pacientes con espasticidad severa, que no habían evolucionado favorablemente con antiespásticos orales, incluyendo altas dosis de baclofeno. Tres de ellos presentaron mejoría importante del dolor, la espasticidad y la calidad de vida, mientras que el otro cursó con síndrome de tolerancia a este medicamento. La bomba intratecal de baclofeno es una intervención útil y segura para pacientes con espasticidad severa que presentan mala respuesta al tratamiento oral o efectos adversos del mismo.
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 poorresponse to oral treatment.
A espasticidade pode causar imobilidade, prostração, dor crônico, úlceras, infeções, trombose e pneumonias; os objetivos do tratamento são controlar ador, melhorar a mobilidade e a qualidade de vida e reincorporar ao doente a suas atividades cotidianas por meio de medicamentos anti-espásticos orais; embora, os pacientes com espasticidade severa podem requerer altas doses orais destes medicamentos eapresentar efeitos adversos, pelo que se há planteado o uso do baclofeno por via intratecal; na Colômbia não se há usado amplamente esta intervenção e não existem protocolos sobre as indicações para levá-la a cabo. O objetivo desta série de casos é apresentar a experiência da Fundação Cardiovascular de Colômbia no tratamento com bombas intratecais de baclofeno de quatro doentes com espasticidade severa, que não haviam evolucionado favoravelmente com anti-espásticos orais, incluindo altas dose de baclofeno. Três deles apresentaram melhoria importante da dor, a espasticidade e a qualidade de vida, enquanto que o outro cursou com síndrome de tolerância a este medicamento. a bomba intratecal de baclofeno é uma intervenção útil e segura para doentes com espasticidade severa que apresentam má resposta aotratamento oral ou efeitos adversos do mesmo.