TIME COURSE OF THE DISTRIBUTION OF MORPHINE IN BRAIN-REGIONS AND SPINAL-CORD AFTER INTRAVENOUS-INJECTION TO SPONTANEOUSLY HYPERTENSIVE AND NORMOTENSIVE WISTAR-KYOTO RATS

Previous studies from this laboratory have demonstrated that the analgesic and hyperthermic effects of morphine were found to be greater in spontaneously hypertensive (SHR) rats than in normotensive Wistar-Kyoto (WKY) rats. The enhanced response to morphine could not be explained on the basis of any of the pharmacokinetic parameters of morphine in the serum. In order to determine the possible contribution of altered distribution of morphine in the central nervous system in the differences in the pharmacological response to morphine in the two strains, the time course of the distribution of morphine was determined in brain regions and spinal cord after its i.v. administration. SHR and WKY rats were injected with morphine (10 mg/kg). At various times (5, 30, 60, 120 and 360 min) after the injection of morphine, brain regions (hypothalamus, cortex, hippocampus, midbrain, pons and medulla, striatum and amygdala) and spinal cord were collected. The level of morphine in the tissues was determined by using a highly sensitive and specific radioimmunoassay method. Five minutes after morphine injection, the concentration of morphine was the highest in the spinal cord. Among the brain regions, the highest concentration of morphine was in the hypothalamus and the lowest in the amygdala. In all the brain regions and spinal cord, the concentration of morphine was significantly higher in the SHR than in the WKY rats. Similar effects were observed at 30, 60 and 120 min after morphine injection. At 360 min, the hypothalamus, cortex and spinal cord of the SHR rats had higher concentrations of morphine than the WKY rats, but the other regions did not show differences in the morphine levels. The tissue to serum ratio was higher in all brain regions at 5 min after morphine injection. Many brain regions collected during the 30-min to 6-hr time period had tissue to serum morphine ratios higher in SHR than in WKY rats. The approximate half-life of morphine in brain regions and spinal cord of WKY rats ranged from 44 to 72 min. In the hypothalamus, pons and medulla, cortex and spinal cord, the half-life of morphine in SHR rats was significantly greater than in WKY rats. It is concluded that the enhanced response to morphine in SHR rats in comparison to WKY rats may, in part, be related to greater levels of morphine in brain regions and spinal cord. This is in addition to greater opioid receptor density in the brain of SHR than in WKY rats which has been demonstrated previously in this laboratory.