RESUMO
Despite significant progress, many uncertainties remain regarding molecular and cellular mechanisms governing opiate tolerance. We report that loss of EphB2 receptor reverse signaling results in a marked acceleration of morphine tolerance in vivo. EphB2 null mice exhibited no significant difference in brain or blood morphine metabolism, mu opiate receptor affinity or binding capacity. Motor and sensory performance for EphB2 null mice was also comparable to controls for both morphine naïve or tolerized states. Regional distributions of mu opioid receptor, CGRP and substance P were also unaltered in EphB2 null mice. However EphB2 null mice, but not animals homozygous for kinase dead version of EphB2, exhibited significant modification of context-dependent anti-nociceptive responses following chronic morphine treatment. To verify the changes seen in EphB2 null mice arise from impairment of hippocampal learning, discreet bilateral lesions of the dorsal hippocampus were produced in wildtype mice demonstrating striking similarities to that seen in EphB2 null mice for opiate-dependent behavior. The results demonstrate that EphB2 reverse signaling plays a unique and requisite role in inhibiting the development of opiate-dependent tolerance in vivo.
Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Aprendizagem/fisiologia , Receptor EphB2/metabolismo , Analgésicos Opioides/farmacocinética , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos Knockout , Morfina/farmacocinética , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/metabolismo , Percepção da Dor/efeitos dos fármacos , Percepção da Dor/fisiologia , Receptor EphB2/genética , Receptores Opioides mu/metabolismo , Substância P/metabolismoRESUMO
Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. Children with Down syndrome are highly susceptible to infantile spasms. The Ts65Dn mouse is a valid model for Down syndrome; therefore, we tested the hypothesis that the Ts65Dn mouse represents a substrate for an animal model of infantile spasms. The baseline of naïve Ts65Dn mice showed spontaneous spike-and-wave discharges, a pattern that worsened with baclofen and gamma-butyrolactone, which induced acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG. GABABR-agonist-induced AEES were significantly reduced with vigabatrin, rodent ACTH fragment, valproic acid, ethosuximide, and CGP 35348. Porcine ACTH had no effect. GABABR protein expression was significantly increased in the thalamus and medulla oblongata of Ts65D mice in comparison with wild-type controls. The GABABR agonist-treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder. GABABR-mediated mechanisms may contribute to the increased susceptibility of children with Down syndrome to infantile spasms.
Assuntos
4-Butirolactona , Baclofeno , Encéfalo/metabolismo , Síndrome de Down/complicações , Agonistas GABAérgicos , Receptores de GABA-B/metabolismo , Espasmos Infantis/induzido quimicamente , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Síndrome de Down/tratamento farmacológico , Síndrome de Down/genética , Síndrome de Down/fisiopatologia , Eletroencefalografia , Etossuximida/farmacologia , Genótipo , Humanos , Lactente , Camundongos , Camundongos Mutantes , Compostos Organofosforados/farmacologia , Fenótipo , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Receptores de GABA-B/efeitos dos fármacos , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Espasmos Infantis/prevenção & controle , Fatores de Tempo , Ácido Valproico/farmacologia , Vigabatrina/farmacologiaRESUMO
The phenomenal proliferation of scientific studies into the nature of induced pluripotent stem (iPS) cells following publication of the findings of Takahashi and Yamanaka little more than 2 years ago, have significantly expanded our understanding of cellular mechanisms relating to cell lineage, differentiation, and proliferation. While the full potential of iPS cell lineages for both scientific tool and therapeutic applications is as yet unclear, findings from several lines of investigation suggests that multipotential and terminally differentiated cells from an array of cell types are competent to undergo epigenetic reprogramming to a pluripotential state. The nature of this pluripotential state appears to be similar to, but not identical with that previously described for embryonic stem (ES) cells. Understanding the nature of this induced reprogrammed state will be critical to determining the full potential of iPS cells. Recently, this issue has been examined through an integrated analysis of the genome in fully and partially reprogrammed iPS cell lineages. These results provide a window onto the temporal components of reprogramming and suggest mechanisms by which the efficacy of reprogramming can be enhanced.