Amino acid incorporation during morphine intoxication. I : Dose and time effects of morphine on protein synthesis in specific regions of the rat brain and in astroglia‐enriched primary cultures

Uptake and incorporation of 3 H‐valine into soluble protein were studies in normal and in physically dependent rat brain, or in astroglial primary cultures at various times after the administration of morphine at different doses. There was an increased protein synthesis in striatum and brain stem of previously untreated rats 2–3 hr after low‐dose morphine administration (10mg/kg bw IP). The changes were completely reversed by naloxone (5 mg/kg bw, IP) administered 10 min prior to the morphine. During the first hour after IP administration of 25 mg morphine/kg bw there was a decrease in striatum and brain stem protein synthesis, followed by an increase in brain stem protein synthesis between 2 and 3 hr later. These changes were blocked by naloxone. In all brain regions studied 40 mg morphine/ 1kg bw, IP inhibited protein synthesis, an effect partially reversed by naloxone (5 mg/kg bw, IP). Similar dose‐ and time‐dependent effects were pbtained from primary astrogliaenriched cultures from cerebral hemispheres, suggesting that low or moderate doses of morphine affect brain cell protein synthesis. At least one phase of increased synthesis was seen, but within a few hours of a high morphine dose the protein synthesis was decreased. After long‐term morphine intoxication (13 days; final dose 340 mg/kg bw/day po) incorporation of 3 H‐valine in vivo into TCA‐precipitable soluble proteins during 60 min decreased in the hypothalamus and in occipital and entorhinal cortex, and was unchanged in other brain regions examined. An IP injection of morphine (10 or 25 mg/kg bw/day) to such animals resulted in a pronounced and rapidly occurring increase in protein synthesis in many brain regions. This was further demonstrated with gel electrophoresis in brain stem and hypothalamus, where higher 3 ‐labeling was seen in many protein bands. The labeling of one band from brain stem having approx 80,000 MW was especially pronounced. Incorporation of 3− H‐valine into mambrance‐bound proteins of brain stem changed in a similar way to the soluble proteins, but was not as pronounced. Similar, although less pronounced, effects were seen after IP administration of 25 mg morphine/kg bw to rats intoxicated for 4 days (final dose 130 mg/kg bw/day po). After an IP injection of 40 mg morphine/kg bw to the long‐term intoxicated rats, the depression in protein synthesis was less pronounced than that seen in previously untreated rats. Naaloxone (5 mg/kg bw IP) gave the rats symptoms of withdrawal. In sensory‐motor cortex and in cerebellum the effects on protein synthesis caused by 10 or 25 mg/kg bw morphine were practically reversed by naloxone, whereas in striatum and brain stem, naloxone in the dose used was not able to compleely restore the changes in protein synthesis. Protein synthesis was not restored to control values in any brain region after naloxone treatment prior to 40 mg morphine/kg bw. After 2 days of withdrawal of morphine‐intoxicated rats, amino acid incorporation into soluble protein increased in the occipital cortex, decreased in the frontal cortex, and was unchanged in the other brain regions examined compared to long‐term‐intoxicated rats. It is concluded that the machinery for protein synthesis is sensitized after long‐term morphine treatment. The sensitization was especially pronounced in brain regions rich in opiate receptors, although it could not be related to the opiate receptor.