No abstract

Centrally administered codeine glucuronide has been shown to exhibit antinociceptive properties with decreased immunosuppressive effects compared to codeine. In this study, codeine-6-glucuronide was administered to rats, and its analgesic effect was compared to that of codeine. The concentrations of codeine and its metabolites in plasma and brain were also determined at the peak response time after administration of each compound. Receptor-binding studies with rat brain homogenates and affinity profiles were also determined. Intravenous administration of codeine-6-glucuronide resulted in approximately 60% of the analgesic response elicited by codeine itself. Analysis of plasma and brain showed that codeine-6-glucuronide is relatively stable in vivo, with only small amounts of morphine-6-glucuronide being detected in addition to unchanged codeine-6-glucuronide. The receptor affinity of codeine-6-glucuronide was similar to that of codeine. It is concluded that intravenously administered codeine-6-glucuronide possesses analgesic activity similar to that of codeine, and may have clinical benefit in the treatment of pain

Phosphorothioated antisense oligodeoxynucleotide (ASODN) targeted to angiotensinogen mRNA was administered intracerebroventricularly in spontaneously hypertensive rats to test whether angiotensinogen reduction would lower their hypertensive blood pressures. The ASODN lowers hypertensive blood pressures to normotensive levels in spontaneously hypertensive rats; sense oligodeoxynucleotide had no effect. Administration of phosphorothioated ASODN produced a prolonged duration of lowered blood pressure. Injections of ASODN at the same dose that decreased hypertension when administered centrally did not result in blood pressure decreases when administered intra-arterially. Furthermore, angiotensinogen production was decreased in the brain stem and significantly decreased in the hypothalamus of the ASODN-treated rats (P < .05), supporting the concept of centrally mediated regulation of hypertension by an overactive brain angiotensin system. To determine the distribution of centrally administered oligodeoxynucleotides, fluorescein isothiocyanate-conjugated oligodeoxynucleotides were injected directly into the lateral ventricles. One hour later, oligodeoxynucleotides were distributed throughout the lateral and third ventricles, with tissue and cellular uptake observed in discrete cells at the injection site. This indicates that the oligodeoxynucleotides are taken up rapidly by brain cells and that they permeate the areas surrounding brain nuclei involved in central blood pressure regulation and volume homeostasis. The results confirm and extend our previous study with phosphodiester ASODN and show that phosphorothioation modification increases the duration of the response and is taken up in vivo. We conclude that with modification, ASODN inhibition of angiotensinogen mRNA translation can be used for a prolonged, profound decrease in mean arterial pressure in the spontaneously hypertensive rat through a central mechanism.