Josep E. Baños

Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain

Neuropathic pain is a clinical manifestation of nerve injury difficult to treat even with potent analgesic compounds. Here, we used different lines of genetically modified mice to clarify the role played by CB2 cannabinoid receptors in the regulation of the central immune responses leading to the development of neuropathic pain. CB2 knock-out mice and wild-type littermates were exposed to sciatic nerve injury, and both genotypes developed a similar hyperalgesia and allodynia in the ipsilateral paw. Most strikingly, knock-outs also developed a contralateral mirror image pain, associated with an enhanced microglial and astrocytic expression in the contralateral spinal horn. In agreement, hyperalgesia, allodynia, and microglial and astrocytic activation induced by sciatic nerve injury were attenuated in transgenic mice overexpressing CB2 receptors. These results demonstrate the crucial role of CB2 cannabinoid receptor in modulating glial activation in response to nerve injury. The enhanced manifestations of neuropathic pain were replicated in irradiated wild-type mice reconstituted with bone marrow cells from CB2 knock-outs, thus demonstrating the implication of the CB2 receptor expressed in hematopoietic cells in the development of neuropathic pain at the spinal cord.

Interferon-γ Is a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain

Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB2 receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury. Thus, neuropathic pain spreads in mice lacking CB2 receptors beyond the site of nerve injury. To further investigate the mechanisms leading to the enhanced manifestation of neuropathic pain, we have established expression profiles of spinal cord tissues from wild-type and CB2-deficient mice after nerve injury. An enhanced interferon-γ (IFN-γ) response was revealed in the absence of CB2 signaling. Immunofluorescence stainings demonstrated an IFN-γ production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB2-deficient mice showed neuronal and astrocytic IFN-γ immunoreactivity also in the contralateral region, thus matching the pattern of nociceptive hypersensitivity in these animals. Experiments in BV-2 microglia cells revealed that transcriptional changes induced by IFN-γ in two key elements for neuropathic pain development, iNOS (inducible nitric oxide synthase) and CCR2, are modulated by CB2 receptor signaling. The most direct support for a functional involvement of IFN-γ as a mediator of CB2 signaling was obtained with a double knock-out mouse strain deficient in CB2 receptors and IFN-γ. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB2 knock-outs. These data clearly demonstrate that the CB2 receptor-mediated control of neuropathic pain is IFN-γ dependent.

Changes of quantal transmitter release caused by gadolinium ions at the frog neuromuscular junction

1 The actions of the trivalent cation, gadolinium (Gd3+), were studied on frog isolated neuromuscular preparations by conventional electrophysiological techniques. 2 Gd3+(450 μm) applied to normal or formamide‐treated cutaneous pectoris nerve‐muscle preparations induced, after a short delay, a complete block of neuromuscular transmission. The reversibility of the effect was dependent on the time of exposure. 3 Gd3+(5–450 μm) had no consistent effect on the resting membrane potential of the muscle fibres. 4 Gd3+(5–40 μm) applied to preparations equilibrated in solutions containing high Mg2+and low Ca2+reduced the mean quantal content of endplate potentials (e.p.ps) in a dose‐dependent manner. Under those conditions, 3,4‐diaminopyridine (10 μm) consistently reversed the depression of evoked quantal release. 5 The calcium current entering motor nerve terminals, revealed after blocking presynaptic potassium currents with tetraethylammonium (10 mm) in the presence of elevated extracellular Ca2+(8 mm), was markedly reduced by Gd3+(0.2–0.5 mm). 6 Gd3+(40–200 μm) increased the frequency of spontaneous miniature endplate potentials (m.e.p.ps) in junctions bathed either in normal Ringer solution or in a nominally Ca2+‐free medium supplemented with 0.7 μm tetrodotoxin. This effect may be due to Gd3+entry into the nerve endings since it is not reversed upon removal of extracellular Gd3+with chelators (1 mm EGTA or EDTA). Gd3+also enhanced the frequency of me.p.ps appearing after each nerve stimulus in junctions bathed in a medium containing high Mg2+and low Ca2+ 7 Gd3+, in concentrations higher than 100 μm, decreased reversibly the amplitude of m.e.p.ps suggesting a postsynaptic action. 8 It is concluded that the block of nerve‐impulse evoked quantal release caused by Gd3+is related to its ability to block the calcium current entering the nerve endings, supporting the view that Gd3+blocks N‐type Ca2+channels; while the enhancement of spontaneous quantal release is probably the result of Gd3+entry into motor nerve endings. Besides its dual prejunctional effects on quantal release it is suggested that Gd3+exerts a postsynaptic action on the endplate acetylcholine receptor‐channel complex.

The endocannabinoid system and neuropathic pain.

Abstract The research of new therapeutic strategies for neuropathic pain represents a major current priority. Important drawbacks to advance in the development of these therapies are the limited translational value of the animal models now available and the elucidation of the complex neuronal and immune pathophysiological mechanisms underlying neuropathic pain. One of the neurotransmitter systems participating in neuropathic pain control that has recently raised a particular interest is the endocannabinoid system. This system is highly expressed in neurons and immune cells, and it plays a crucial role in the development of neuropathic pain. Preclinical studies have provided important findings, revealing the potential interest of the endocannabinoid system for the treatment of neuropathic pain. These studies have reported the analgesic effects of cannabinoid agonists in multiple neuropathic pain models, and they have identified specific targets within this system to develop more effective and safe analgesic compounds. However, further studies using more relevant neuropathic pain animal models are required to confirm these interesting results. Several clinical studies suggest that cannabinoids significantly reduced neuropathic pain, although most of these trials fail the required standards of quality. The different pain patient populations included in the systematic reviews also make it difficult to get adequate conclusions. Therefore, additional clinical trials that consider an adequate number of patients, the use active treatments as controls, and longer duration of administration are required to have an adequate profile of the effectiveness and safety of cannabinoids in neuropathic pain.

Fentanyl as pre-emptive treatment of pain associated with turning mechanically ventilated patients: a randomized controlled feasibility study.

PurposeTo compare pain incidence and changes in pain scores with fentanyl versus placebo as pre-emptive treatment during turning and 30xa0min post-turning in mechanically ventilated critically ill patients.MethodsWe performed a randomized, double-blind, parallel-group, placebo-controlled clinical trial in the intensive care unit of a university hospital. Seventy-five mechanically ventilated patients were randomized to an intervention group (fentanyl) or a control group (placebo). Patients in the intervention group received 1xa0µg/kg (medical patients) or 1.5xa0µg/kg (surgical patients) of fentanyl 10xa0min before turning. Pain indicators were assessed using the behavioral pain scale. Safety was assessed by determining the frequency and severity of pre-defined adverse events. Pain was evaluated at rest (T0), at turn start and end (T1 and T2) and at 5, 15 and 30xa0min post-turning (T3, T4 and T5).ResultsThe two groups had similar baseline characteristics. The area under the curve for BPS values was significantly smaller in the fentanyl group than in the control group [median and interquartile range (IQR): 132 (108–150) vs. 147 (125–180); pxa0=xa00.016, respectively]. Nineteen non-serious adverse events were recorded in 14 patients, with no significant between-group differences (23xa0% fentanyl group vs. 14xa0% control group; pxa0=xa00.381).ConclusionsThese results suggest an intravenous bolus of fentanyl of 1xa0µg/kg for medical patients or 1.5xa0µg/kg for surgical patients reduces the incidence of turning-associated pain in critically ill patients on mechanical ventilation.ClinicalTrials.gov: NCT 01950000.

Usefulness of knockout mice to clarify the role of the opioid system in chronic pain

Several lines of knockout mice deficient in the genes encoding each component of the endogenous opioid system have been used for decades to clarify the specific role of the different opioid receptors and peptide precursors in many physiopathological conditions. The use of these genetically modified mice has improved our knowledge of the specific involvement of each endogenous opioid component in nociceptive transmission during acute and chronic pain conditions. The present review summarizes the recent advances obtained using these genetic tools in understanding the role of the opioid system in the pathophysiological mechanisms underlying chronic pain. Behavioural data obtained in these chronic pain models are discussed considering the peculiarities of the behavioural phenotype of each line of knockout mice. These studies have identified the crucial role of specific components of the opioid system in different manifestations of chronic pain and have also opened new possible therapeutic approaches, such as the development of opioid compounds simultaneously targeting several opioid receptors. However, several questions still remain open and require further experimental effort to be clarified. The novel genetic tools now available to manipulate specific neuronal populations and precise genome editing in mice will facilitate in a near future the elucidation of the role of each component of the endogenous opioid system in chronic pain.

Benefits of using a hybrid problem-based learning curriculum to improve long-term learning acquisition in undergraduate biology education

Although problem-based learning (PBL) has been used for over 40 years, with many studies comparing the benefits of PBL versus other educational approaches, little attention has been paid to the effectiveness of hybrid PBL (H-PBL) curricula. Here we aimed to compare the learning outcomes of two groups of undergraduate biology students working towards a bachelors degree: one group used an H-PBL approach, while the second used a lecture-based learning (LBL) approach. Specifically, the H-PBL group used a PBL module with interdisciplinary problems, which represented 20% of the entire curriculum. The main outcomes of evaluation were the long-term acquisition of factual knowledge and the problem-solving skills at the end of the bachelors degree. The sample included 85 students, 39 in the H-PBL group and 46 in the LBL group. We found that an H-PBL curriculum can improve the students learning outcomes such as long-term knowledge acquisition, problem solving skills and generic competences.

Using feature films as a teaching aid with medical students

ISSN: 0142-159X (Print) 1466-187X (Online) Journal homepage: http://www.tandfonline.com/loi/imte20 Using feature films as a teaching aid with medical students Josep E. Baños & Fèlix Bosch To cite this article: Josep E. Baños & Fèlix Bosch (2015) Using feature films as a teaching aid with medical students, Medical Teacher, 37:9, 883-884, DOI: 10.3109/0142159X.2014.970997 To link to this article: http://dx.doi.org/10.3109/0142159X.2014.970997 Published online: 16 Dec 2014.

Utilidad de las películas para debatir temas complejos: política, religión y ciencia en Ágora

Introduccion. Las peliculas comerciales han constituido un metodo docente de demostrada eficacia en entornos educativos de ciencias de la salud. En el presente articulo se describe la utilidad de Agora para presentar las complejas relaciones entre ciencia, politica y religion, las cuales afectan a diversas situaciones biomedicas en la actualidad. Materiales y metodos. La actividad consistio en la proyeccion de la pelicula y posterior debate, al final del cual los estudiantes cumplimentaron, de forma anonima y voluntaria, un cuestionario de diez preguntas sobre los temas tratados y los vinculados con los objetivos educativos preestablecidos. Despues se les solicito que enviaran voluntariamente un informe personal sobre los aspectos mas relevantes de la pelicula. Resultados. Cincuenta y dos estudiantes (96,3% de los asistentes) respondieron el cuestionario de evaluacion. Consideraron que Agora tenia un interes notable para describir un ejemplo de conflicto entre ciencia y poderes sociales, y manifestaron que tales situaciones aun podian persistir hoy. En los informes personales realizados por 49 estudiantes (90,7%) destacaron la consideracion de tales conflictos, las barreras impuestas al conocimiento nuevo, la discriminacion de la mujer en la sociedad y en la ciencia, asi como las dificultades que entrana el respeto por el pensamiento individual. Conclusiones. Agora puede ser una pelicula de interes para analizar y debatir las dificiles relaciones entre ciencia, religion y politica. A pesar de su ambientacion clasica, plantea situaciones aun identificables en nuestra sociedad y que los estudiantes deberian conocer.

Utilidad de los textos literarios en la docencia de ciencias de la salud: ejemplos en cardiología

espanolLa importancia de las humanidades en la educacion medica es un hecho generalmente aceptado y se ha sugerido su introduccion en los planes de estudio de cursos como los basados en literatura y medicina. A pesar de su viabilidad, existen dificultades en incluir asignaturas especificas en curriculos ya apretados. Se ha planteado la posibilidad de utilizar textos literarios como elementos docentes en las asignaturas tradicionales. Sin embargo, existen pocas publicaciones que analicen la utilidad potencial de algunos de ellos. En el presente articulo se presentan tres obras que podrian emplearse para ilustrar la experiencia de la enfermedad en el caso de las cardiopatias. Se escogieron dos textos autobiograficos, Un infart de miocardi, de Josep Pla, y Monte Sinai, de Jose Luis Sampedro, y uno de ficcion, Memoires d’Hadrien, de Marguerite Yourcenar. Se revisaron para constatar que podian contribuir a comprender la vivencia de la enfermedad por los pacientes y alcanzar los objetivos educativos establecidos. Se presentan los fragmentos escogidos para ilustrar las repercusiones de la enfermedad y se debate la utilidad para la comprension de los aspectos emocionales de la enfermedad y de la relacion medico-paciente. EnglishThe importance of humanities in the medical training is commonly recognized and it has been suggested that its implementation in the medical curricula as literature and medicine courses. In spite of its viability, there is often difficult to include specific subjects in the already crowded medical curricula. Therefore, it has been suggested the use of literary texts as a teaching tool in traditional subjects. However, there are few publications that analyse the potential usefulness of them. In the present paper three literary works that might be used to illustrate the experience of disease in cardiology are discussed. Two autobiographical texts, Un infart de miocardi of Josep Pla and Monte Sinai of Jose Luis Sampedro, and a fiction work, Memoires d’Hadrien of Marguerite Yourcenar, were chosen. They were reviewed to establish their usefulness to understand the patient’s experience of disease and to reach educative objectives. The paper shows the chosen fragments to illustrate the disease consequences and its usefulness to understand emotional aspects of sickness and the patient-physician relationship is discussed.