Differential effects of acute and prolonged morphine withdrawal on motivational and goal-directed control over reward-seeking behaviour.

Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

Model of negative affect induced by withdrawal from acute and chronic morphine administration in male mice.

Opioid use disorder (OUD) is a chronic relapsing disorder that is a major burden for the lives of affected individuals, and society as a whole. Opioid withdrawal is characterized by strong physical symptoms, along with signs of negative affect. Negative affect due to opioid withdrawal is a major obstacle to recovery and relapse prevention. The mechanisms behind negative affect due to either spontaneous or antagonist-precipitated opioid withdrawal are not well known, and more animal models need be developed. Here, we present behavioral models of negative affect upon naloxone-precipitated morphine withdrawal in adult male mice. Social, anxiety, and despair-like deficits were investigated following naloxone administration in mice receiving morphine under three dosing regimens; acute, chronic constant dose and chronic escalating doses. Social behaviour in the three-chamber social preference test was decreased following withdrawal from chronic and escalating but not acute morphine. Anxiety-like behaviour in the open field was increased for all three treatments. Despair-like behaviour was increased following withdrawal from chronic and escalating but not acute morphine. Altogether, these animal models will contribute to study behavioural and neuronal circuitries involved in the several negative affective signs characterizing OUD.

Representações sociais de pessoas com câncer em cuidados paliativos sobre a morfina / Social representations of people with cancer in palliative care on morphine

INTRODUÇÃO: A dor se apresenta como sintoma frequente nas pessoas com câncer, e os opioides são os fármacos de escolha para o seu alívio. Dentre eles tem-se a morfina, que é um dos mais utilizados. OBJETIVOS: Descrever as representações sociais de pessoas com câncer em cuidados paliativos sobre a morfina; Analisar tais representações e suas implicações para a adesão ou não a esse opioide no tratamento/alívio da dor do câncer; Propor estratégias de cuidados afinadas às representações das pessoas com câncer que requerem o uso de morfina. MÉTODO: Pesquisa com abordagem qualitativa, do tipo descritiva e exploratória, realizada em uma instituição pública hospitalar. Os participantes foram pessoas com câncer atendidas no Ambulatório. Critérios de inclusão: maiores de 18 anos, com índice ≥ 50% na Escala de Karnofsky (KPS) e prescrição analgésica de morfina. Critérios de exclusão: presença de dor de moderada a intensa no momento da coleta de dados; e aqueles com comprometimento verbal, cognitivo e/ou psiquiátrico. Os dados foram coletados por questionário e entrevista semiestruturada. Os dados do questionário foram analisados por estatística descritiva simples e percentual, e aos conteúdos verbais aplicou-se a análise de conteúdo do tipo lexical, com o uso do software Alceste. Projeto aprovado pelos Comitês de Ética em Pesquisa da instituição proponente e cooperante, com pareceres no 3.296.128 e no 3.453.968, respectivamente. Todos os participantes assinaram o Termo de Consentimento Livre e Esclarecido. RESULTADOS: A média de idade foi de 54,7 anos; sexo feminino (69,7%); predomínio da religião evangélica (60,6%); 81,8% afirmaram seguir corretamente a prescrição da morfina; na Escala de Karnofsky, 45,5% apresentaram índice de 60%, evidenciando a necessidade de assistência ocasional, mas com capacidade de trabalhar; a intensidade da dor pela escala visual analógica variou entre leve (grau 1) e moderada (grau 4), ambas com 21,2% de respostas. O processamento dos dados no Alceste gerou dois blocos, o primeiro com a Classe 1, que expressa a representação medicamentosa do tratamento com a morfina e os fatores associados a esse tratamento; o segundo foi composto pelas Classes 2 e 3 e expressam as relações sociais envolvidas no contexto do tratamento, o vínculo da pessoa que usa morfina com o mundo que a cerca, bem como a relação estabelecida com esse medicamento, o conhecimento sobre a morfina e as atitudes adotadas diante desse uso. Houve ambiguidade nas representações da morfina, colocando-a entre a dor e o temor, pois a indicam como um importante recurso para alívio/tratamento da dor do câncer, mas sinalizam que também pode trazer repercussões negativas associadas aos seus efeitos. CONSIDERAÇÕES FINAIS: Apesar de haver aderência dos pacientes à morfina, a opiofobia ainda precisa ser combatida por meio de estratégias que façam circular informações que possam reconstruir representações sobre a morfina e seu uso terapêutico. A educação terapêutica por meio da atuação de equipe multidisciplinar se destaca como uma boa estratégia de difusão de informações seguras sobre o uso de opioides.

INTRODUCTION: Pain is a frequent symptom in people with cancer, and opioids are the drug of choice for its relief, including morphine, which is one of the most used. OBJECTIVES: To describe the social representations of people with cancer in palliative care about morphine; To analyze such representations and their implications for adherence or not to this opioid in the cancer pain treatment/relief; To propose care strategies related to the representations of people with cancer that require the use of morphine. METHOD: Descriptive and exploratory research with a qualitative approach, carried out in a public hospital. The participants were people with cancer treated at the clinic. Inclusion criteria: over 18 years old, with an index ≥ 50% on the Karnofsky Scale (KPS) and morphine as an analgesic medication prescribed. Exclusion criteria: presence of moderate to severe pain at the time of data collection; and those with verbal, cognitive and/or psychiatric impairment. Data was collected by questionnaire and semi-structured interview. The questionnaire data were analyzed using simple and percentage descriptive statistics, and the verbal content was analyzed using lexical content with the Alceste software. Project approved by the Research Ethics Committees of the proposing and cooperating institution, with opinions No. 3,296,128 and 3,453,968, respectively. All participants signed the Free and Informed Consent Form. RESULTS: The average age was 54.7 years; female gender (69.7%); prevalence of the evangelical religion (60.6%); 81.8% said they correctly followed the prescription of morphine; on the Karnofsky Scale, 45.5% had an index of 60% showing the need for occasional assistance, but with the ability to work; pain intensity by visual analog scale ranged from mild (grade 1) to moderate (grade 4), both with 21.2% responses. The data processing at Alceste generated two blocks, the first with class 1, which expresses the drug representation of the treatment with morphine and the factors associated with that treatment; the second was composed of Classes 2 and 3 and expresses the social relationships involved in the context of the treatment, the bond of the person who uses morphine with the world around her, as well as the relationship established with this medicine, the knowledge about the morphine and the attitudes towards the use of the medicine. There was ambiguity in the representations of morphine, placing it between pain and fear, as they indicate it as an important resource to relieve/treat cancer pain, but it can also bring negative repercussions associated with its effects. FINAL CONSIDERATIONS: Despite patient adherence to morphine, opiophobia still needs to be fought through strategies that spread information that can reconstruct representations about morphine and its therapeutic use. Therapeutic education through the work of a multidisciplinary team stands out as a good strategy to disseminate safe information about the use of opioids.

INTRODUCCIÓN: El dolor es un síntoma frecuente en las personas con cáncer y los opioides son los fármacos de elección para su alivio; entre ellos está la morfina, que es uno de los más utilizados. OBJETIVOS: Describir las representaciones sociales de las personas con cáncer en cuidados paliativos sobre la morfina; analizar tales representaciones y sus implicaciones para la adherencia o no a este opioide en el tratamiento / alivio del dolor producido por el cáncer; Proponer estrategias de cuidados en sintonía con las representaciones de las personas con cáncer que requieren el uso de morfina. MÉTODO: Investigación con enfoque cualitativo, descriptivo y exploratorio, realizada en un hospital público. Los participantes fueron personas con cáncer tratadas en modalidad ambulatorial. Criterios de inclusión: mayores de 18 años, con índice ≥ 50% en la Escala de Karnofsky (KPS) y prescripción analgésica de morfina. Criterios de exclusión: presencia de dolor de moderado a intenso en el momento de la recogida de datos; y aquellos con comprometimiento verbal, cognitivo y/o psiquiátrico. Datos recogidos mediante cuestionario y entrevista semiestructurada. Los datos del cuestionario se analizaron mediante estadística descriptiva simple y porcentual y el contenido verbal fue sometido a análisis de contenido de tipo lexical, utilizándose el software Alceste. Proyecto aprobado por los Comités de Ética en Investigación de la institución proponente y cooperante, con dictámenes núm. 3.296.128 y 3.453.968, respectivamente. Todos los participantes firmaron una declaración de Consentimiento Libre e Informado. RESULTADOS: La edad promedio fue de 54,7 años; sexo femenino (69,7%); predominio de la religión evangélica (60,6%). El 81,8% afirmó que seguía correctamente la prescripción de morfina. En la Escala de Karnofsky, el 45,5% presentó un índice del 60%, lo que indica la necesidad de asistencia ocasional, pero con capacidad para trabajar. La intensidad del dolor, según la escala visual analógica (EVA), varió de leve (grado 1) a moderado (grado 4), ambos con 21,2% de respuestas. El procesamiento de datos en el software Alceste generó dos bloques: el primero con la Clase 1, que expresa la representación farmacológica del tratamiento con morfina y los factores asociados a ese tratamiento; el segundo estaba compuesto por las Clases 2 y 3 y expresa las relaciones sociales involucradas en el contexto del tratamiento, el vínculo de la persona que usa morfina con el mundo que la rodea, así como la relación que establece con ese medicamento, el conocimiento sobre la morfina y las actitudes adoptadas con respecto a su uso. Hubo ambigüedad en las representaciones de la morfina, pues se la situó entre el dolor y el miedo: los participantes la señalaron como un recurso importante para el alivio/tratamiento del dolor oncológico, pero también mencionaron la posibilidad de repercusiones negativas asociadas a sus efectos. CONSIDERACIONES FINALES: A pesar de la adherencia de los pacientes a la morfina, la opiofobia aún debe combatirse mediante estrategias que hagan circular información que permita la reconstrucción de las representaciones sobre la morfina y su uso terapéutico. La educación terapéutica mediante la actuación de un equipo multidisciplinario descolla como una buena estrategia para difundir información segura sobre el uso de opioides.

Efectos de la morfina en la plasticidad cerebral / Effects of morphine on brain plasticity

Introducción: La morfina, como otros opiáceos y las drogas de abuso, tiene la capacidad de modificar la plasticidad cerebral de las áreas que regulan la morfología neuronal de las dendritas y espinas, que son el sitio primario de sinapsis excitatorias en regiones cerebrales que regulan funciones de incentivo motivación, recompensa y aprendizaje. Objetivo: En la presente revisión se analizan aspectos del impacto del uso de la morfina durante los periodos prenatales del desarrollo cerebral y las consecuencias a largo plazo en murinos, para relacionar estos efectos que ocurren en el humano neonato y adulto. Desarrollo: La exposición repetida a la morfina en el tratamiento del dolor en enfermos terminales produce cambios a largo plazo en la densidad postsináptica de sitios (dendritas y espinas) en áreas sensibles del cerebro, como la corteza prefrontal y el sistema límbico (hipocampo, amígdala), así como en los núcleos caudado y accumbens. Este artículo revisa los mecanismos celulares implicados, principalmente de los receptores dopaminérgicos y glutamatérgicos, así como la plasticidad sináptica lograda por los cambios en las dendritas y espinas en esta área. Conclusiones: Las acciones de la morfina durante el desarrollo del cerebro y también en el cerebro adulto producen alteraciones en la plasticidad de sitios excitatorios postsinápticos, áreas del cerebro que están implicadas en las funciones del sistema límbico (la recompensa y el aprendizaje). Se necesitan más estudios sobre la plasticidad en las dendritas y espinas en sus moléculas de señalización, tales como el calcio, con el fin de mejorar el tratamiento de la adicción

Introduction: Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are the primary sites of excitatory synapses in regions of the brain involved in incentive motivation, rewards, and learning. Objective: In this review we discuss the impact of morphine use during the prenatal period of brain development and its long-term consequences in murines, and then link those consequences to similar effects occurring in human neonates and adults. Development: Repeated exposure to morphine as treatment for pain in terminally ill patients produces long-term changes in the density of postsynaptic sites (dendrites and spines) in sensitive areas of the brain, such as the prefrontal cortex, the limbic system (hippocampus, amygdala), and caudate nuclei and nucleus accumbens. This article reviews the cellular mechanisms and receptors involved, primarily dopaminergic and glutamatergic receptors, as well as synaptic plasticity brought about by changes in dendritic spines in these areas. Conclusions: The actions of morphine on both developing and adult brains produce alterations in the plasticity of excitatory postsynaptic sites of the brain areas involved in limbic system functions (reward and learning). Doctors need further studies on plasticity in dendrites and spines and on signaling molecules, such as calcium, in order to improve treatments for addiction