Sleep disorders increase pain sensitivity and the risk of developing painful conditions; however, the underlying mechanisms are poorly understood. It has been suggested that nucleus accumbens (NAc) influences sleep-wake cycle by means of a balance between adenosine activity at A2A receptors and dopamine activity at D2 receptors. Because the NAc also plays an important role in pain modulation, we hypothesized that the NAc and its A2A and D2 receptors mediate the pronociceptive effect of rapid eye movement (REM) sleep deprivation (SD). We found that 24 hours of REM-SD induced an intense pronociceptive effect in Wistar rats, which decreases progressively over a sleep rebound period. Although the level of fecal glucocorticoid metabolites increased with SD within group, it did not differ between sleep-deprived group and control group, indicating a stress response with similar magnitude between groups. The pronociceptive effect of REM-SD was prevented by excitotoxic lesion (N-Methyl-D-aspartate, 5.5 μg) of NAc and reverted by its acute blockade (Qx-314, 2%). The administration of an A2A receptor antagonist (SCH-58261, 7 ng) or a D2 receptor agonist (piribedil, 6 μg) into the NAc increased home cage activity and blocked the pronociceptive effect of REM-SD. Complementarily, an A2A receptor agonist (CGS-21680, 24 ng) impaired the reversal of the pronociceptive effect and decreased home cage activity, as it did a D2 receptor antagonist (raclopride, 5 μg). Rapid eye movement SD did not affect the expression of c-Fos protein in NAc. These data suggest that SD increases pain by increasing NAc adenosinergic A2A activity and by decreasing NAc dopaminergic D2 activity.
The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not known. In this study, we asked whether PSD increases tonic nociception in the formalin test, decreases the antinociceptive effect of morphine administered into the periaqueductal gray matter (PAG), and disrupts endogenous descending pain modulation. PSD for either 24 or 48 h significantly increased formalin-induced nociception and decreased mechanical nociceptive paw withdrawal threshold. The maximal antinociceptive effect induced by morphine (0.9-9 nmol, intra-PAG) was significantly decreased by PSD. The administration of a low dose of the GABAA receptor antagonist, bicuculline (30-300 pmol, intra-PAG), decreased nociception in control rats, but not in paradoxical-sleep-deprived ones. Furthermore, the administration of the cholecystokinin (CCK) 2 receptor antagonist, YM022 (0.5-2 pmol) in the rostral ventral medulla (RVM), decreased nociception in paradoxical-sleep-deprived rats but not in control ones. While a dose of the CCK 2 receptor agonist, CCK-8 (8-24 pmol intra-RVM), increased nociception in control rats, but not in paradoxical-sleep-deprived ones. In addition, the injection of lidocaine (QX-314, 2%, intra-RVM) decreased nociception in sleep-deprived rats, but not in control rats, while the lesion of the dorsolateral funiculus prevented the pronociceptive effect of PSD. Finally, PSD significantly increased c-Fos expression in the RVM. Therefore, PSD increases pain independently of its duration or of the characteristic of the nociceptive stimulus and decreases morphine analgesia at the PAG. PSD appears to increase pain by decreasing descending pain inhibitory activity and by increasing descending pain facilitatory activity.
The ability to modulate pain perception is as critical to survival as pain itself. The most known pain modulation pathway is the PAG-RVM (periaqueductal gray-rostral ventromedial medulla) descending system. In this study, we hypothesized that it is functionally linked to the ascending nociceptive control, which is a form of pain-induced analgesia dependent on mesolimbic mechanisms. To test this hypothesis, we used a pharmacological approach, in which the antinociception induced by noxious stimulation (forepaw injection of capsaicin) was detected in a standard rat model of inflammatory pain (hindpaw injection of carrageenan). This antinociception was blocked by interventions known to block the ascending nociceptive control-mediated analgesia: the blockade of μ-opioid (Cys,Tyr,Orn,Penamide (CTOP) 0.5 μg) or of dopamine (SCH23390 1.8 μg and raclopride 5 μg) receptors within the NAc (nucleus accumbens) and that of cholinergic nicotinic receptors (mecamylamine 0.6 μg) within the RVM. The antinociception was also blocked by standard interventions known to block mechanisms of descending inhibition within either the PAG or the RVM: local acute neuronal blockade (lidocaine 2%), blockade of μ-opioid receptors (CTOP 0.5 μg), or activation of GABA receptors (muscimol 10 ng). Consistently, interventions that are known to block spinal mechanisms of descending inhibition also blocked antinociception: lesion of dorsolateral funiculus and the spinal blockade of serotonergic (WAY100135 46 μg or tropisetron 10 μg) or adrenergic (idazoxan, 50 μg) receptors. Neuronal activity indirectly estimated by c-Fos expression within the NAc, PAG, and RVM supports behavioral observations. Therefore, this study provides functional data indicating that noxious stimulation triggers an ascending-descending pain modulation pathway linking the mesolimbic system to the PAG-RVM descending system.
As important as perceiving pain is the ability to modulate this perception in some contextual salient situations. The periaqueductal gray (PAG) is perhaps the most important site of endogenous pain modulation; however, little is known about dopaminergic mechanisms underlying PAG-mediated antinociception. In this study, we used a pharmacological approach to evaluate this subject. We found that µ-opioid receptor-induced antinociception (DAMGO, 0.3 μg) from PAG was blocked by the coadministration of either D1-like or D2-like dopaminergic antagonists (SCH23390, 2, 4, and 6 μg or raclopride, 2 and 4 μg, respectively) both in the tail-flick and in the mechanical paw-withdrawal test. A selective D2-like receptor agonist (piribedil, 6 and 12 μg into the PAG) induced antinociception in the mechanical paw-withdrawal test, but not in the tail-flick test. This effect was blocked by the coadministration of its selective antagonist (raclopride 4 μg), as well as by either a GABAA agonist (muscimol, 0.1 μg) or an opioid receptor antagonist (naloxone, 0.5 μg). A selective D1-like receptor agonist (SKF38393, 1, 5, and 10 μg into the PAG) induced a poor and transient antinociceptive effect, but when combined with piribedil, a potentiated antinociceptive effect emerged. None of these treatments affected locomotion in the open-field test. These findings suggest that µ-opioid antinociception from the PAG depends on dopamine acting on both D1-like and D2-like receptors. Selective activation of PAG D2-like receptors induces antinociception mediated by supraspinal mechanisms dependent on inhibition of GABAA and activation of opioid neurotransmission.
The endogenous ability to decrease pain perception during life-threatening situations is crucial to the prevention of recuperative behaviors and to leave the subject free to engage in appropriated defensive responses. We have previously shown that acute pain activates the ascending nociceptive control—an endogenous analgesia circuit dependent on opioid mechanisms within nucleus accumbens—to facilitate the tonic immobility response, an innate defensive behavior. Now we asked whether chronic pain and pain chronification impairs either the tonic immobility response or the ability of acute pain to facilitate it by activating the ascending nociceptive control. We found a significant decrease in the duration of the tonic immobility response in rats during the induction and maintenance phases of the persistent mechanical hyperalgesia. This finding suggests that chronic pain and its development impair defensive responses. However, during the induction and maintenance phases of persistent hyperalgesia, the ascending nociceptive control activation, by a forepaw capsaicin injection, increased the tonic immobility response, an effect prevented by the blockade of μ-opioid receptors within nucleus accumbens. This finding suggests that pain chronification and chronic pain do not prevent the ability of acute pain to facilitate the defensive behavior of tonic immobility by activating the ascending nociceptive control. Therefore, although chronic pain states decrease the ability to engage in a defensive behavior, they may not prevent the expression of defensive behaviors during life-threatening situations accompanied by acute pain. The biological purpose of such a mechanism may be to increase the chances of survival of a wounded subject exposed to acute pain in a novel life-threatening situation.
O projeto “Fisiologia na educação de jovens para cidadania” visou ampliar a formação cidadã de jovens e consiste no planejamento, aplicação e avaliação de aulas (teórico- práticas), abrangendo 10 temas, estimulando o autocuidado e o conhecimento do corpo humano. As aulas foram ministradas em duas instituições parceiras situadas em Curitiba: Centro Sócio Educativo Padre Giocondo e Projeto Abrindo Caminhos. O projeto contribuiu para (i) ampliar a formação dos acadêmicos de enfermagem e medicina da UFPR; (ii) fornecer materiais didáticos e treinamento aos educadores das instituições parceiras; (iii) coletar e analisar dados sobre as condições gerais de saúde, habitação e saneamento dos jovens e seus vizinhos, obtidos através de um questionário. Os temas de aulas (p. ex., O corpo humano, Ritmos biológicos) foram abordados de maneira expositiva dialogada e através de várias atividades práticas durante as quais observa-se grande participação dos jovens. Neste artigo são apresentadas estas atividades, bem como sua ordem de preferência segundo os adolescentes. Finalmente, são discutidos os dados relevantes obtidos a partir do questionário, e sua relação com as ações deste projeto. Palavras-chave: Educação, Atividades práticas, Corpo humano, Adolescentes, Cidadania. Interactive pedagogical instruments for the teaching of physiology and health basic concepts for teenagers Abstract: The Project “Physiology in Young Education for Citizenship” aimed at expanding civic educationto young people and encompassing the planning, implementation and evaluation of theoretical and practical classes on 10 main themes by promoting self-care and human body knowledge. The classes were held in two partner institutions located in Curitiba, Paraná State: Centro Sócio Educativo Padre Giocondo and Projeto Abrindo Caminhos. The project contributed towards expanding the training of scholars in the Nursing and Medicine courses at UFPR University. Furthermore, the initiative provided educational materials and training for educators from partner institutions, and collected and analyzed data obtained through a survey on the overall health, housing and sanitation conditions of young people and their neighbors. The themes approached in the classes (e.g., “The human body”, and “Biological Rhythms”) were presented by dialogued lectures and several practical activities during which there was a great deal of participation of young people. In the present article such activities are described, as well as their rank of preference among the adolescents. Finally, the data from the survey instrument used to assess health, housing and sanitation conditions are presented, and their relation with the Project activities are discussed. Key words: Education, Practical Learning Activities, Human Body, Adolescents, Citizenship. Herramientas educacionales interactivas para la enseñanza de la Fisiologia y nociones básicas de la salud para los jóvenes Resumen: El Proyecto "Fisiología en la educación de jóvenes para la ciudadanía" fue dirigido a incrementar la educación cívica de los jóvenes y consiste en la planificación, ejecución y evaluación de clases (prácticas y teóricas), que abarcaran 10 temas, estimulando el auto cuidado y el conocimiento del cuerpo humano. Las clases fueron dictadas en dos instituciones asociadas ubicadas en la ciudad de Curitiba: Centro Sócio Educativo Padre Giocondo y Projeto Abrindo Caminhos. El proyecto contribuyó para: (i) ampliar la formación de los estudiantes de Enfermería y Medicina de la Universidade Federal do Paraná; (ii) proporcionar materiales educativos y de formación para los educadores de las instituciones asociadas; (iii) recoger y analizar datos sobre la salud en general, la vivienda y el saneamiento de los jóvenes y sus vecinos, obtenidos a través de un cuestionario. Los temas de las clases (p. Ej., “El cuerpo humano”, “Los ritmos biológicos”) se discutieron a través de exposiciones dialogadas y a través de diversas actividades prácticas, en que se observa una gran participación de los jóvenes. En este artículo se presenta este tipo de actividades, así como su grado de preferencia entre los adolescentes. Finalmente, se presentan los datos del instrumento de la encuesta sobre las condiciones de salud, vivienda y saneamiento, y se discuten su relación con las actividades del proyecto. Palabras-clave: Educación, Actividades de Aprendizaje Práctico, Cuerpo Humano, Adolescentes, Ciudadanía.
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