THE EFFECTS OF MORPHINE TREATMENT AND MORPHINE-WITHDRAWAL ON THE DYNORPHIN AND ENKEPHALIN SYSTEMS IN SPRAGUE-DAWLEY RATS

The effect of morphine tolerance and withdrawal on prodynorphin peptid es was studied in relevant brain areas and in the pituitary gland of m ale Sprague-Dawley rats, and compared with effects on the proenkephali n-derived peptide Met-enkephalin. After 8 days of morphine injections (twice daily), dynorphin A and B levels increased in the nucleus accum bens and dynorphin A levels increased also in the striatum. Morphine t reatment increased-striatal Met-enkephalin. Leu-enkephalinArg(6) level s were reduced in the ventral tegmental area (VTA). Morphine-treated r ats had very low Leu-enkephalinArg(6) levels in the hippocampus as com pared to saline control rats. Comparison of the relative amounts of dy norphin peptides and the shorter prodynorphin-derived peptides, Leu-en kephalinArg(6) and Leu-enkephalin, revealed a relative increase in dyn orphin peptides versus shorter fragments in the nucleus accumbens, VTA and hippocampus. Morphine-tolerant rats had lower levels of dynorphin A in both lobes of the pituitary gland, whereas hypothalamic dynorphi n levels were unaffected by morphine. Leu-enkephalinArg(6) levels were reduced in the hypothalamus, but not changed in the pituitary gland. Naloxone-precipitated withdrawal accentuated the increase in dynorphin A and B levels in the accumbens and dynorphin A levels in the striatu m, while inducing an increase in enkephalin levels in the accumbens an d Met-enkephalin in the VTA. In the hippocampus, Leu-enkephalinArg(6) levels remained low in the withdrawal state. The low dynorphin levels in the anterior part of the pituitary gland were reversed by naloxone, whereas the low dynorphin A levels in the neurointermediate lobe were even lower in the withdrawal state. In conclusion, morphine tolerance and withdrawal affected prodynorphin-derived peptides in areas relate d to central reward mechanisms, and in the pituitary gland. The dynorp hin peptides and the Leu-enkephalinArg(6) fragment were not affected s imilarly, indicating an effect also on metabolic interconversion.