RESUMO
The dopaminergic mesocorticolimbic system plays an important role in the reinforcing effects of ethanol. Opioid peptides modulate the activity of this system and have been suggested to mediate, at least in part, the reinforcing properties of ethanol. Thus, beta-endorphin (beta-END) could participate in the development of ethanol reinforcement and addiction. The aim of this work was to investigate the acute and chronic ethanol effects on beta-END content in regions of the mesolimbic system and to examine if chronic ethanol treatment alters ligand binding to mu opioid receptor (muOR). Male Wistar rats received a single acute ethanol dose of 2.5 g/kg or water by intra-gastric administration. For chronic ethanol treatment experiments, one group of rats was given ethanol (10% v/v solution) to drink, two groups were given equivalent volumes of sucrose (14.14% isocaloric solution) or water, respectively, and a fourth group had ad libitum access to food and water. Treatment was followed for 4 weeks. Beta-endorphin content in brain regions was quantified by radioimmunoassay and ligand binding studies to muOR were performed by quantitative autoradiography using 8 nM [(3)H]-DAMGO as radioligand. Acute ethanol decreased beta-END content in the hypothalamus (26%) 1h after administration. No ethanol effects were observed in the midbrain, ventral tegmental area, substantia nigra, nucleus accumbens, nucleus accumbens-septum and prefrontal cortex. Chronic ethanol treatment neither changed beta-END levels nor [(3)H]-DAMGO binding to mu opioid receptors in any of the regions studied. However, beta-END levels in the sucrose group were significantly increased in the nucleus accumbens and substantia nigra, in comparison to all other groups. These findings suggest that different neural mechanisms and specific brain regions may be involved in the reinforcing effects of ethanol and sucrose.
Assuntos
Química Encefálica/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/metabolismo , Etanol/farmacologia , beta-Endorfina/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Dopamina/fisiologia , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/metabolismo , Radioimunoensaio , Ratos , Ratos Wistar , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Sacarose/farmacologiaRESUMO
There is no information concerning signal transduction mechanisms downstream of the opioid/nociceptin receptors in the human epileptic brain. The aim of this work was to evaluate the level of G-proteins activation mediated by DAMGO (a mu receptor selective peptide) and nociceptin, and the binding to mu and nociceptin (NOP) receptors and adenylyl cyclase (AC) in neocortex of patients with pharmacoresistant temporal lobe epilepsy. Patients with temporal lobe epilepsy associated with mesial sclerosis (MTLE) or secondary to tumor or vascular lesion showed enhanced [3H]DAMGO and [3H]forskolin binding, lower DAMGO-stimulated [35S]GTPgammaS binding and no significant changes in nociceptin-stimulated G-protein. [3H]Nociceptin binding was lower in patients with MTLE. Age of seizure onset correlated positively with [3H]DAMGO binding and DAMGO-stimulated [35S]GTPgammaS binding, whereas epilepsy duration correlated negatively with [3H]DAMGO and [3H]nociceptin binding, and positively with [3H]forskolin binding. In conclusion, our present data obtained from neocortex of epileptic patients provide strong evidence that a) temporal lobe epilepsy is associated with alterations in mu opioid and NOP receptor binding and signal transduction mechanisms downstream of these receptors, and b) clinical aspects may play an important role on these receptor changes.
Assuntos
Epilepsia do Lobo Temporal/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Neocórtex/metabolismo , Receptores Opioides mu/metabolismo , Receptores Opioides/metabolismo , Lobo Temporal/metabolismo , Adenilil Ciclases/metabolismo , Adulto , Fármacos do Sistema Nervoso Central/farmacologia , Colforsina/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/metabolismo , Feminino , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Opioides/metabolismo , Radioisótopos de Enxofre , Trítio , Adulto Jovem , Receptor de Nociceptina , NociceptinaRESUMO
Previous studies have established a relationship between sleep disruption and pain, and it has been suggested that hyperalgesia induced by paradoxical sleep deprivation (PSD) could be due to a reduction of opioidergic neurotransmission in the brain. In the present study rats deprived of sleep for 96 h as well as rats allowed to recover for 24h after PSD and normal controls received vehicle or morphine (2.5, 5 and 10 mg/kg, i.p.) and were tested on a hot plate 1h later. Quantitative receptor autoradiography was used to map alterations in binding to brain mu-opioid receptors in separate groups. Results demonstrated that PSD induced a significant reduction in thermal pain threshold, as measured by paw withdrawal latencies. This effect did not return to baseline control values after 24h of sleep recovery. The usual analgesic effect of morphine was observed in the control group but not in PSD or rebound groups except at the highest dose (10 mg/kg). Binding of [3H]DAMGO to mu sites did not differ significantly among the three groups in any of the 33 brain regions examined. These results do not exclude the participation of the opioid system in PSD-induced pain hypersensitivity since sleep-deprived rats were clearly resistant to morphine. However, the fact no changes were seen in [3H]DAMGO binding indicates that mechanisms other than altered mu-opioid binding must be sought to explain the phenomenon.
Assuntos
Encéfalo/metabolismo , Hiperalgesia/metabolismo , Limiar da Dor/fisiologia , Receptores Opioides mu/metabolismo , Privação do Sono/complicações , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/metabolismo , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Temperatura Alta , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Morfina/metabolismo , Morfina/farmacologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Opioides mu/efeitos dos fármacos , Estatísticas não ParamétricasRESUMO
The present work sought to study the binding properties of central mu-opiate receptors in whole brain and in different central areas in adult rats undernourished at perinatal age. Rats were undernourished with a hypoproteic diet containing 8% casein from day 14 of gestation until 50 days of age. The animals were thereafter fed a balanced commercial chow until 140 days of age. At this time point the experiments started. 3H-D-Ala2, N-Me-Phe4, Gly5-ol-enkephalin (3H-DAMGO) was used to selectively label the mu-receptors. The results obtained demonstrated that perinatal undernutrition induced, in the adult animal, a decreased mu-receptors density (Bmax) both in whole brain as well as in midbrain, without significant changes in affinity. In addition, no changes were found in mu-specific binding in the cortex of these undernourished animals. Taking into account that recent evidences from our laboratory have demonstrated a lower stress-induced analgesia following exposure to different stressful situations in rats undernourished in early life, the present findings seem to suggest that this lower analgesic response could be due, at least in part, to a lower density of mu-opiate receptors in the brain.
Assuntos
Animais Recém-Nascidos , Encéfalo/metabolismo , Proteínas Alimentares/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal , Deficiência de Proteína/complicações , Receptores Opioides mu/metabolismo , Analgesia , Animais , Caseínas/administração & dosagem , Ala(2)-MePhe(4)-Gly(5)-Encefalina/metabolismo , Feminino , Idade Gestacional , Masculino , Gravidez , Ratos , Ratos Wistar , Estresse Fisiológico , TrítioRESUMO
Biochemical and pharmacological evidence suggest that the dopaminergic mesolimbic system plays a key role in mediating the reinforcing properties of alcohol and other drugs of abuse. Alcohol reinforcement and high alcohol drinking behavior have been postulated to be partially mediated by a neurobiological mechanism involving the alcohol-induced activation of the endogenous opioid system. The aim of this work was to study the effect of the in vivo acute administration of ethanol on mu (mu) opioid receptors in the rat dopaminergic meso-accumbens and mesocortical pathways by quantitative receptor autoradiography. [(3)H]DAMGO binding was significantly decreased in the ventral tegmental area (VTA) 30 min after ethanol administration. A small ethanol-induced reduction was observed in the shell region of the nucleus accumbens 1 h after exposure. In contrast, 2 h after ethanol administration, [(3)H]DAMGO binding was significantly increased in the frontal and prefrontal cortices. The observed changes correlated well with high ethanol plasma levels. Our results suggest that the reinforcing properties of ethanol may be partially mediated by mechanisms involving the ethanol-induced down- and up-regulation of mu receptors in the dopaminergic mesolimbic system. Mu receptors in the VTA and the frontal and prefrontal cortices may be involved in the in vivo acute responses to ethanol and could play a key role in modulating the dopaminergic activity of the mesocortical pathway in response to the drug. In contrast, the contribution of both mu and delta receptors in the nucleus accumbens might be relevant in these processes.