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

Generic Algorithm to Predict the Speed of Translational Elongation: Implications for Protein Biogenesis

Synonymous codon usage and variations in the level of isoaccepting tRNAs exert a powerful selective force on translation fidelity. We have developed an algorithm to evaluate the relative rate of translation which allows large-scale comparisons of the non-uniform translation rate on the protein biogenesis. Using the complete genomes of Escherichia coli and Bacillus subtilis we show that stretches of codons pairing to minor tRNAs form putative sites to locally attenuate translation; thereby the tendency is to cluster in near proximity whereas long contiguous stretches of slow-translating triplets are avoided. The presence of slow-translating segments positively correlates with the protein length irrespective of the protein abundance. The slow-translating clusters are predominantly located down-stream of the domain boundaries presumably to fine-tune translational accuracy with the folding fidelity of multidomain proteins. Translation attenuation patterns at highly structurally and functionally conserved domains are preserved across the species suggesting a concerted selective pressure on the codon selection and species-specific tRNA abundance in these regions