The effects of intra-accumbal administration of the nicotinic acetylcholine receptor agonist cytisine on the operant oral self-administration of ethanol were prevented by the GABAB receptor agonist baclofen in rats.

RATIONALE: Although the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. METHODS: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. RESULTS: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. CONCLUSIONS: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.

Baclofen prevents morphine rewarding effects and associated biochemical alterations in male and female mice.

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.

Involvement of Pre-limbic Cortex-Nucleus accumbens projections in Context-Induced alcohol seeking.

Alcohol use disorder (AUD) remains a critical public health issue worldwide, characterized by high relapse rates often triggered by contextual cues. This research investigates the neural mechanisms behind context-induced reinstatement of alcohol-seeking behavior, focusing on the nucleus accumbens and its interactions with the prelimbic cortex, employing Male Long-Evans rats in an ABA renewal model. In our experimental setup, rats were trained to self-administer 10 % ethanol in Context A, followed by extinction of lever pressing in the presence of discrete cues in Context B. The context-induced reinstatement of ethanol-seeking was then assessed by re-exposing rats to Context A or B under extinction conditions, aiming to simulate the environmental cues' influence on relapse behaviors. Three experiments were conducted: Experiment 1 utilized Fos-immunohistochemistry to examine neuronal activation in the nucleus accumbens; Experiment 2 applied the baclofen + muscimol inactivation technique to probe the functional importance of the nucleus accumbens core; Experiment 3 used Fos-immunofluorescence along with Retrobeads injection to investigate activation of neurons projecting from the prelimbic cortex to the nucleus accumbens core. Our findings revealed significant increases in Fos-immunoreactive nuclei within the nucleus accumbens core and shell during the reinstatement phase in Context A, underscoring the environment's potent effect on ethanol-seeking behavior. Additionally, inactivation of the nucleus accumbens core markedly reduced reinstatement, and there was a notable activation of neurons from the prelimbic cortex to the nucleus accumbens core in the ethanol-associated context. These results highlight the critical role of the nucleus accumbens core and its corticostriatal projections in the neural circuitry underlying context-driven ethanol seeking.

History and evolution of surgical treatment for spasticity: a journey from neurotomy to selective dorsal rhizotomy.

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.

Publication Trends of Research on Intrathecal Baclofen Therapy: A Bibliometric Analysis of the Literature.

OBJECTIVE: The objective of this study was to analyze the trends in publications on intrathecal baclofen (ITB) therapy. METHODS: We searched Elsevier's Scopus database in February 2022 to find articles focused on ITB therapy. Data extracted included citation count, publication year, author's country and income category, journal and its 5-year impact factor, research type, disease requiring ITB, and target population. RESULTS: The analysis covered 615 articles from 1985 to 2022. The average citation count per article was 27.47 (95% confidence interval 23.75-31.18) and the mean impact factor was 4.54 (95% confidence interval 3.84-5.24). The majority (76.42%) were primary research, with 8.1% being interventional and 91.9% observational. Even so, one half of the top ten most cited were interventional. Secondary research and case reports made up 12.68% and 10.73% respectively, with narrative reviews making up most of the secondary research (79.48%). Only 1 study conducted a meta-analysis. The United States was the most prolific country. High-income countries published 96.42% of articles. CONCLUSIONS: The rising number of ITB articles and citations indicates growing interest and expanding knowledge in this field. However, there's a notable scarcity of research from low- and middle-income countries, particularly those with high prevalence of ITB-treatable diseases. The need for more evidence to overcome potential barriers to ITB implementation is emphasized. Despite an increasing number of publications, a large proportion presented low levels of evidence, such as case reports and narrative reviews, highlighting the need for more rigorous research methods to solidify the evidence base for ITB therapy.

Intracerebroventricular baclofen therapy improves function and quality of life in a child with severe cerebral palsy.

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.

Anti-proliferative and anti-inflammatory effects of the application of baclofen cream, a GABAB receptor agonist, on skin inflammation in mice.

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.

Development, Quality by Design-Based Optimization, and Stability Assessment of Oral Liquid Formulations Containing Baclofen for Hospital Use.

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.

Baclofeno para o tratamento da espasticidade / Baclofen for or treatment of spasticity

INTRODUÇÃO: A espasticidade é caracterizada por ser um distúrbio motor relacionado a reflexos de estiramento tônico (tônus muscular) com espasmos tendinosos exagerados. É sintoma frequente de outras condições que afetam o sistema nervoso central (SNC), então a incidência e a prevalência variam de acordo com elas, bem como gravidade, músculos afetados, tempo de acometimento pela doença e tratamento. No Brasil, no âmbito do Sistema Único de Saúde (SUS), o tratamento da espasticidade é direcionado pelo Protocolo Clínico e Diretrizes Terapêuticas de Espasticidade (2017), cuja principal terapia farmacológica abordada é a toxina botulínica do tipo A. Tendo isso em vista e o fato do baclofeno ser uma tecnologia utilizada na clínica para casos de espasticidade, o presente relatório foi elaborado com o objetivo de compreender a viabilidade do uso de baclofeno de administração oral no manejo da espasticidade para pacientes adultos, visando a incorporação do fármaco no SUS. TECNOLOGIA: Baclofeno oral. PERGUNTA: O uso de baclofeno de administração oral é eficaz, seguro e custo-efetivo para o tratamento de espasticidade em pacientes adultos? EVIDÊNCIAS CLÍNICAS: Foi realizada uma revisão sistemática da literatura com o objetivo de identificar todos os estudos clínicos randomizados (ECRs) que avaliassem a eficácia e segurança do baclofeno oral em comparação com as terapias atualmente disponíveis no SUS para pacientes adultos com espasticidade. No total, foram incluídos 09 ECRs, sendo sete comparando o baclofeno com placebo e dois comparando o medicamento com diazepam. Na avaliação, não foi possível a condução de uma metanálise ou qualquer outro tipo de análise estatística que sintetize as informações apresentadas pelos ECRs devido à heterogeneidade dos estudos em relação aos desfechos e a forma de medi-los/relatá-los. Quando comparado ao placebo, apesar dos resultados de parte dos ECRs indicarem tendência de melhora com o baclofeno, a diferença de efeito não era estatisticamente significativa para certos desfechos. Em relação ao diazepam, nenhum estudo demonstrou diferença estatisticamente significativa entre os dois medicamentos no que diz respeito à melhora da espasticidade. Para todos dos desfechos de interesse analisados, os ECRs apresentaram alto risco de viés, principalmente por problemas relacionados às etapas de randomização, sigilo de alocação e cegamento (ausência de descrição ou relato inadequado). AVALIAÇÃO ECONÔMICA: Foi elaborado um modelo de custo-minimização no qual se considerou a mesma probabilidade de melhora da espasticidade do baclofeno oral mais terapia padrão e da terapia padrão isolada. A análise econômica conduzida baseou-se em um modelo de árvore de decisão que projetou a relação entre custo da intervenção (baclofeno oral + terapia padrão) e do comparador (terapia padrão) durante um ano. O resultado da análise de custo-minimização foi de aumento de custo com o tratamento com o baclofeno, sendo R$ 85,72 por paciente. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A incorporação do baclofeno oral, no SUS, geraria um impacto incremental de R$ 955 mil no primeiro ano de incorporação, totalizando um incremento de R$ 4,7 milhões em 5 anos se a taxa de difusão for 30%. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: No horizonte considerado nesta análise, não foram detectadas tecnologias para o tratamento de espasticidade. CONSIDERAÇÕES FINAIS: Há limitação das evidências científicas que demonstram melhora da espasticidade com a utilização do baclofeno oral, o que pode ser, em parte, explicada pela data de condução dos estudos clínicos e do início da comercialização do medicamento na década de 1970. As limitações acabam por se estender para as análises econômicas, as quais foram baseadas em apenas um estudo clínico que não conseguiu demonstrar os benefícios clínicos do uso do medicamento. Por outro lado, o baclofeno apresentou um custo incremental relativamente baixo, de R$ 85,72 por paciente, em comparação à terapia padrão. Apesar das incertezas em relação à eficácia do baclofeno, ele é um medicamento de uso consolidado na prática clínica, para o qual não há evidência de eventos adversos graves, a sua dose tende a ser adaptada individualmente e, mesmo com a incerteza, diretrizes internacionais relatam que o seu uso é uma das alternativas terapêuticas para o tratamento da espasticidade. Além disso, entende-se que o impacto orçamentário incremental estimado da incorporação do baclofeno não afeta significativamente a sustentabilidade do SUS. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Plenário da Conitec, em sua 102ª Reunião Ordinária, realizada no dia 06 de outubro de 2021, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação do baclofeno oral para o tratamento da espasticidade. Para essa recomendação, a Conitec considerou que a evidência clínica é escassa, de baixa qualidade e não é demonstrada a superioridade do medicamento em relação ao placebo. Apesar da larga experiência de uso e diretrizes internacionais citando o baclofeno oral como alternativa, essas recomendações não são suportadas por evidências. A matéria foi disponibilizada em Consulta Pública. CONSULTA PÚBLICA: Foi realizada entre os dias 04/11/2021 e 23/11/2021. Foram recebidas 22 constribuições, sendo quatro pelo formulário para contribuições técnico-científicas e 18 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Após apreciação de todas elas, o Plenário da Conitec entendeu que não houve argumentação suficiente para mudança de entendimento acerca de sua recomendação preliminar, que foi desfavorável à incorporação da tecnologia no SUS. RECOMENDAÇÃO FINAL DA CONITEC: Pelo exposto, o Plenário da Conitec, em sua 105ª Reunião Ordinária, no dia 10 de fevereiro de 2022, deliberou por unanimidade recomendar a não incorporação de baclofeno para o tratamento de pacientes adultos com espasticidade no SUS. Os membros da Conitec consideraram escassas as evidências científicas disponíveis, além de antigas e de não mostrar efeito benéfico muito superior ao comparador analisado. Lembraram dos valores pouco expressivos das análises de custo-efetividade e de impacto-orçamentário, mas isso não mudou a posição sobre a não incorporação. Por fim, foi assinado o Registro de Deliberação nº 711/2022. DECISÃO: Não incorporar o baclofeno oral para o tratamento da espasticidade, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 25, publicada no Diário Oficial da União nº 52, seção 1, página 74, em 17 de março de 2022.

Baclofen and catatonia: a case report.

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.

Efficacy and safety of tolperisone versus baclofen among Chinese patients with spasticity associated with spinal cord injury: a non-randomized retrospective study.

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).

GABAB receptors blockage modulates somatic and aversive manifestations induced by nicotine withdrawal.

There is substantial evidence that GABAB agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue vulnerabilities in humans. In this context, we explored different aspects associated with the possible mechanisms whereby the GABAB receptors might influence nicotine withdrawal. Male mice received nicotine (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. Nicotine-treated mice received the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC, 2 or 3.5 mg/kg, s.c.), to precipitate the withdrawal state. A second group of dependent mice received 2-hydroxysaclofen (GABAB receptor antagonist, 1 mg/kg, s.c.) before MEC-precipitated abstinence. Somatic signs of nicotine withdrawal were measured for 30 min. Anxiogenic-like response associated to nicotine withdrawal was assessed by the elevated plus maze test. The dysphoric/aversive effect induced by nicotine withdrawal was evaluated using conditioned place aversion paradigm. Dopamine, serotonin and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. Finally, α4ß2 nicotinic acetylcholine receptor density was determined in several brain regions using autoradiography assays. The results showed that MEC-precipitated nicotine withdrawal induced somatic manifestations, anxiogenic-like response and dysphoric/aversive effect, and 2-hydroxysaclofen potentiated these behavioral responses. Additionally, 2-hydroxysaclofen was able to change striatal dopamine levels and α4ß2 nicotinic acetylcholine receptor density, both altered by MEC-precipitated nicotine withdrawal. These findings provide important contributions to elucidate neurobiological mechanisms implicated in nicotine withdrawal. We suggest that GABAB receptor activity is necessary to control alterations induced by nicotine withdrawal, which supports the idea of targeting GABAB receptors to treat tobacco addiction in humans.

Baclofen pump with pre-brainstem catheter tip placement: technical note and case series.

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.

Efficacy and safety of tolperisone versus baclofen among Chinese patients with spasticity associated with spinal cord injury: a non-randomized retrospective study

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).

Síndrome de persona rígida: presentación de caso clínico y abordaje terapéutico / Stiff man Syndrome Clinical case presentation and therapeutic approach

Introducción: El síndrome del hombre rígido representa una rara enfermedad neuromuscular caracterizada por rigidez muscular progresiva y espasmos musculares dolorosos que afecta a 1 persona por cada millón de habitantes por año en el mundo. En la mayoría de los pacientes se encuentran niveles elevados de anticuerpos descarboxilasa del ácido glutámico. En Colombia solo se han publicado alrededor de 3 casos, lo que motiva la presentación de un nuevo informe que aporte a la discusión actual en el campo de la neurología clínica. Caso clínico: Paciente de sexo femenino de 35 años con cuadro clínico progresivo de varios años, caracterizado por contracciones paroxísticas dolorosas, parestesias y pérdida de fuerza. Se documentó la presencia de anticuerpos anti-GAD compatibles con el síndrome del hombre rígido. Tras un tratamiento integral, que incluyó la infusión farmacológicamente intratecal con baclofeno, se obtuvo mejoría clínica en el índice de Barthel. Conclusiones: El síndrome del hombre rígido es una condición infradiagnosticada que se asocia a un deterioro de la calidad de vida de quienes lo padecen.

Introduction: Stiff man syndrome represents a rare neuromuscular disease characterized by progressive muscle rigidity and painful muscle spasms that affects 1 person for every million habitants per year in the world. High levels of glutamic acid antibodies decarboxylase are found in most patients. In Colombia, only around 3 cases have been published, which motivates the presentation of a new report that contributes to the current discussion in the field of clinical neurology. Clinical Case: 35-year-old female patient with a progressive clinical picture of several years, characterized by painful paroxysmal contractions, paresthesias and loss of strength. The presence of anti-GAD antibodies was documented, compatible with Stiff man syndrome. After comprehensive treatment, which included pharmacologically intrathecal infusion with baclofen, clinical improvement was obtained in the Barthel index. Conclusions: Stiff man syndrome is an underdiagnosed condition which is associated with a deterioration in the quality of life for those who suffer from it.

Effect of coadministration of the GABAB agonist baclofen and the 5-HT2C agonist Ro60-0175 on the expression of amphetamine-induced locomotor sensitization.

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.

GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches.

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 9 mg/kg, s.c.) administration using both pharmacological (BAC 2 mg/kg, i.p.; and 2-OH-saclofen, SAC 0.3 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.

Modulation of tonic immobility by GABAA and GABAB receptors of the medial amygdala.

Tonic immobility (TI) is a temporary state of profound motor inhibition associated with great danger as the attack of a predator. Previous studies carried out in our laboratory evidenced high Fos-IR in the posteroventral region of the medial nucleus of the amygdala (MEA) after induction of the TI response. Here, we investigated the effects of GABAA and GABAB of the MEA on TI duration. Intra-MEA injections of the GABAA agonist muscimol and GABAB agonist baclofen reduced TI response, while intra-MEA injections of the GABAA antagonist bicuculline and GABAB antagonist phaclofen increased the TI response. Moreover, the effects observed with muscimol and baclofen administrations into MEA were blocked by pretreatment with bicuculline and phaclofen (at ineffective doses per se). Finally, the activation of GABAA and GABAB receptors in the MEA did not alter the spontaneous motor activity in the open field test. These data support the role of the GABAergic system of the MEA in the modulation of innate fear.