Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Levantamento de dados sobre o conhecimento e informação acerca dos medicamentos genéricos em uma população de pacientes do serviço de saúde ambulatorial do Recife, Pernambuco, Brasil Knowledge and information concerning generic drugs in a public outpatient population in Recife, Pernambuco, Brazil

A Lei nº. 9.787/99, que regulamenta os medicamentos genéricos, contempla normas para o registro e prevê a expansão do acesso da população a medicamentos seguros, eficazes, com qualidade e baixo custo. Após um quadriênio da introdução dos genéricos no Brasil, propõe-se verificar o conhecimento e a informação sobre genéricos entre os usuários dos serviços públicos de saúde ambulatorial do Recife, Pernambuco. No ano de 2002, foi aplicado um questionário pré-elaborado. Dos entrevistados, 76,1% eram do sexo feminino. Ouviram falar sobre o "medicamento genérico" 95,7% e 68,1% conheciam o medicamento genérico. As ações adotadas pelo governo, quanto à divulgação das propriedades desta especialidade farmacêutica e às vantagens oferecidas ao consumidor, atingiram sobremaneira esta população.<br>Brazilian Federal Act 9,787/99, regulating generic medicines, includes rules for drug registration and provides for the population's access to safe, effective, high-quality, and low-cost medication. Four years after the introduction of generic drugs on the Brazilian market, we proposed to measure knowledge and information on generic drugs among the clientele at a public outpatient clinic in Recife, Pernambuco State, applying a questionnaire in 2000. 76.1% of the interviewees were women, 95.7% had heard of generic drugs, and 68.1% could define generic medication. Government action to publicize the properties of such medicines and their advantages for consumers has thus reached the vast majority of the population

Contribution of adenylyl cyclase modulation of pre- and postsynaptic GABA neurotransmission to morphine antinociception and tolerance

Opioid inhibition of presynaptic GABA release in the ventrolateral periaqueductal gray (vlPAG) activates the descending antinociception pathway. Tolerance to repeated opioid administration is associated with upregulation of adenylyl cyclase activity. The objective of these studies was to test the hypothesis that adenylyl cyclase contributes to opioid tolerance by modulating GABA neurotransmission. Repeated microinjections of morphine or the adenylyl cyclase activator NKH477 into the vlPAG decreased morphine antinociception as would be expected with the development of tolerance. Conversely, microinjection of the adenylyl cyclase inhibitor SQ22536 reversed both the development and expression of morphine tolerance. These behavioral results indicate that morphine tolerance is dependent on adenylyl cyclase activation. Electrophysiological experiments revealed that acute activation of adenylyl cyclase with forskolin increased the frequency of presynaptic GABA release. However, recordings from rats treated with repeated morphine administration did not exhibit increased basal miniature inhibitory postsynaptic current (mIPSC) frequency but showed a decrease in mean amplitude of mIPSCs indicating that repeated morphine administration modulates postsynaptic GABAA receptors without affecting the probability of presynaptic GABA release. SQ22536 reversed this change in mIPSC amplitude and inhibited mIPSC frequency selectively in morphine tolerant rats. Repeated morphine or NKH477 administration also decreased antinociception induced by microinjection of the GABAA receptor antagonist bicuculline, further demonstrating changes in GABA neurotransmission with morphine tolerance. These results show that the upregulation of adenylyl cyclase caused by repeated vlPAG morphine administration produces antinociceptive tolerance by modulating both pre- and postsynaptic GABA neurotransmission