RESUMO
Opioid medications are frequently used in the effective treatment of intractable pain, but prolonged use of such medications can be complicated by a host of adverse effects. Among these adverse effects, tolerance and mental clouding can be especially disabling and can lead to both a reduced effectiveness of treatment and a reduced quality of life for many requiring treatment with these medications. Here we examined the relative contributions of complete Freund's adjuvant (CFA)-induced inflammatory pain and opioid medication on spatial memory for a well-learned task in male Sprague-Dawley rats. Although CFA, by itself, had little effect on spatial memory, morphine administered to pain-free animals produced profound detrimental effects on spatial memory that persisted longer than the analgesic effectiveness of the drug. However, no significant cognitive deficits were observed in animals receiving morphine in the presence of CFA-induced pain. Taken together, these results are evidence that the pain state of the organism can alter some of the negative effects of morphine.
Assuntos
Dor Crônica , Transtornos Cognitivos/induzido quimicamente , Memória/efeitos dos fármacos , Morfina/toxicidade , Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Huntington's disease (HD) is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein is ubiquitously expressed in HD patients, cellular degeneration occurs predominantly in neurons within the corpus striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent in vitro work suggests that Rhes may be a co-factor with mutant huntingtin in cell death. The objective of the present study was to examine whether the inhibition of Rhes would attenuate or delay the symptoms of HD in vivo. We used a transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD(+)/Rhes(-/-) mice showed significantly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD.
Assuntos
Comportamento Animal , Proteínas de Ligação ao GTP/deficiência , Proteínas de Ligação ao GTP/genética , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Animais , Peso Corporal/genética , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Distonia/complicações , Feminino , Técnicas de Inativação de Genes , Humanos , Proteína Huntingtina , Doença de Huntington/complicações , Doença de Huntington/genética , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
Rhes, the Ras Homolog Enriched in Striatum, is an intermediate-size GTP binding protein. Although its full functions are not yet known, it has been shown to affect signaling and behaviors mediated by G protein-coupled receptors. Here we have tested whether Rhes affects behaviors mediated by opioid receptors. Wild type and rhes-deficient mice were administered morphine and tested for analgesia in formalin and tail flick tests. Rhesâ»/â» mice showed significantly enhanced analgesia in both tests relative to rhes+/+ mice. Furthermore, rhesâ»/â» mice did not display tolerance to repeated morphine administration and displayed significantly less withdrawal than rhes+/+ mice. These findings indicate that Rhes is involved in behaviors mediated by mu opioid receptors and in the adaptive response to repeated morphine administration.
