ABSTRACT
RATIONALE: Cancer patients receiving the antineoplastic drug paclitaxel report higher incidences and longer duration of treatment-resistant depression than patients receiving other classes of chemotherapeutics. Rodents treated with paclitaxel exhibit a suite of changes in affect-like behaviors. Further, paclitaxel causes chemotherapy-induced peripheral neuropathy (CIPN) in humans and rodents. Kappa opioid receptors (KOR) have a well-established role in depression and neuropathy. The contributions of KOR signaling to paclitaxel-induced aversive-like state and CIPN in rodents remain to be explored. OBJECTIVES: We aimed to investigate whether dysregulation of the KOR/dynorphin system is associated with paclitaxel-mediated pain-like behavior and depression-like behavior. METHODS: Cancer-free male C57BL/6J mice were treated with four injections of vehicle or paclitaxel (32 mg/kg cumulative). The effects of the selective KOR antagonist norbinaltorphimine (norBNI) on paclitaxel-induced sucrose preference deficits and mechanical hypersensitivity were measured. Prodynorphin mRNA and receptor-mediated G protein activation were measured at two time points following the last paclitaxel injection using quantitative real-time polymerase chain reaction and agonist-stimulated [35S]guanosine-5'-O'-(γ-thio)-triphosphate ([35S]GTPγS) binding, respectively, in the nucleus accumbens (NAc), caudate-putamen, amygdala, and spinal cord. RESULTS: Paclitaxel produced a norBNI-reversible sucrose preference deficit, whereas mechanical hypersensitivity was not reversed by norBNI. Paclitaxel treatment increased the levels of mRNA for prodynorphin, a precursor for endogenous KOR agonists, in the NAc. Paclitaxel also had time-dependent effects on KOR-mediated G protein activation in the NAc. CONCLUSIONS: These results suggest that KOR signaling mediates an initial aversive component of paclitaxel, but not necessarily paclitaxel-induced mechanical hypersensitivity.
Subject(s)
Antineoplastic Agents, Phytogenic/toxicity , Avoidance Learning/drug effects , Paclitaxel/toxicity , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/metabolism , Receptors, Opioid, kappa/metabolism , Amygdala/drug effects , Amygdala/metabolism , Animals , Avoidance Learning/physiology , Dose-Response Relationship, Drug , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Male , Mice , Mice, Inbred C57BL , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolismABSTRACT
Patient care in an intensive care unit (ICU) is associated with an increased risk of developing nosocomial infections. Bacteremia is responsible for a great number of cases, 23% of which have attributable mortality in developed countries and can affect up to 52% of ICU patients. The main cause of mortality is inadequate and inappropriate antimicrobial empirical therapy. The incorrect use of antimicrobials is a major risk for identifying multidrug resistant microorganisms, thereby involving increased morbidity, mortality and costs. Implementing several surveillance systems and becoming acquainted with resistance patterns represent a valuable tool for identifying, preventing and treating this infectious complication. There is paucity of data regarding antimicrobial resistance in bacteremic patients in Latin America, and the available data reveals a worrying scenario.
Subject(s)
Anti-Infective Agents/therapeutic use , Bacteremia/drug therapy , Drug Resistance, Bacterial , Inappropriate Prescribing , Humans , Intensive Care Units , Latin AmericaABSTRACT
Patient care in an intensive care unit (ICU) is associated with an increased risk of developing nosocomial infections. Bacteremia is responsible for a great number of cases, 23% of which have attributable mortality in developed countries and can affect up to 52% of ICU patients. The main cause of mortality is inadequate and inappropriate antimicrobial empirical therapy. The incorrect use of antimicrobials is a major risk for identifying multidrug resistant microorganisms, thereby involving increased morbidity, mortality and costs. Implementing several surveillance systems and becoming acquainted with resistance patterns represent a valuable tool for identifying, preventing and treating this infectious complication. There is paucity of data regarding antimicrobial resistance in bacteremic patients in Latin America, and the available data reveals a worrying scenario.
El manejo médico en la unidad de cuidado intensivo (UCI) se asocia con un mayor riesgo de infecciones intrahospitalarias. Las bacteriemias tienen una alta frecuencia en dichas unidades, se presentan hasta en el 52% de los pacientes allí asistidos y en los países desarrollados se les atribuye una mortalidad del 23%, que se debe fundamentalmente al uso de tratamiento empírico inadecuado o inapropiado. El uso incorrecto de los antimicrobianos es uno de los principales factores de riesgo para el desarrollo de la resistencia bacteriana, que conlleva la selección de microorganismos multirresistentes, el aumento de la morbilidad y la mortalidad y el incremento en los días de estancia hospitalaria y del costo por hospitalización. La implementación de diferentes sistemas de vigilancia y el conocimiento de la variabilidad en la resistencia a los antimicrobianos constituyen valiosas herramientas para identificar y prevenir la resistencia a los antibióticos y para orientar la terapéutica. En América Latina disponemos de pocos datos sobre las tasas de resistencia y aquellos disponibles muestran un panorama preocupante.
