Disposition of morphine in rat brain: relationship to biological activity.

The levels of morphine in plasma and brain subcortex of rats were determined by gas-liquid chromatography and radioimmunoassay at various time intervals after a single i.v. injection of graded doses of morphine (0.44, 1.04 and 2.25 mg/kg). The disappearance curve of morphine plasma levels appeared to be composed of at least two exponential terms: a rapid disappearance during the 1st hr, which was dependent on the unit dose of morphine injected and a slower disappearance rate after the 1st hr. The highest morphine levels in the brain were measured already 5 min after its injection and these levels only slightly decreased over the next 2 hr. Thereafter a more rapid disappearance of brain morphine was observed. The brain/plasma ratio gradually increased from 0.18 at 5 min after injection to about 1.0 at 60 and 120 min and decreased to approximately 0.4 at 4 hr after injection. This may suggest that morphine is retained in the brain during the 1st hr after injection and that it might be removed from the brain between 2 and 4 hr, possibly by an active process. The relationship between brain morphine levels and the degree of antinociception as assessed with the hot plate procedure appeared to be rather complicated. Shortly after morphine injection, but also at 60 and 120 min after injection, the antinociceptive effect was much lower than might be expected from the levels of morphine in the brain. Several possible explanations for this phenomenon are discussed. A high dose of naltrexone, which completely blocked the antinociceptive effect of morphine, did not affect brain and plasma levels of morphine. Rifampicin, which attenuates development of morphine tolerance, increased brain levels of morphine but did not change plasma levels. Pretreatment with the tripeptide prolyl-leucyl-glycinamide, which facilitates development of morphine tolerance, decreased brain morphine levels and increased plasma levels at 3 hr after morphine injection. This suggests that tolerance development and the rate with which morphine is removed from the brain may have at least some common underlying mechanisms.

Adrenocorticotrophic hormone fragments mimic the effect of morphine in vitro.

1 Fragments of the N terminal part of adrenocorticotrophic hormone (ACTH) inhibited the electrically evoked contractions of the mouse vas deferens. This inhibition could be antagonized by naloxone. 2 The same fragments displaced radiolabelled morphine from morphine antiserum. 3 Structure-activity relationship studies showed that in both assay systems the active core is located within the sequence ACTH 7--10. 4 It is postulated that the Trp9 residue and the peptide bond between Trp9 and Gly10 are particularly important for interaction of ACTH fragments with morphine receptors.