Our data support the view that the mechanism of the long-term adaptation to high doses of morphine is primarily based on desensitization of opioid receptors-response preferentially oriented to mu- and delta-opioid receptors. Prolonged exposure of rats to high doses of morphine results in decrease of the over-all output of opioid receptors-stimulated G-protein activity in the forebrain cortex but does not decrease the amount of these regulatory proteins.