The mechanisms involved in the development of morphine tolerance and dependence are still unknown. Recently much attention has been directed toward the changes in post receptor events. Opiate receptors, like other hormone and neurotransmitter receptors, have been shown to mediate their effects through guanine nucleotide binding proteins (G-proteins). This, in turn, may cause alterations in intracellular events, one of which is transcription of specific genes. We investigated the changes in the levels of mRNA of proenkephalin (PPE) and prodynorphin (DYN) and the stirnulatory G protein alpha subunit (Gas) in adult morphine tolerant rats. Chronic morphine treatment induced reciprocal alterations in the levels of opioid peptide mRNA and G,, mRNA in discrete brain regions. In striatum, PPE mRNA decreased by 49% ( P < -01) and in hypothalamus, DYN mRNA showed a decrease of 21% (P < .01). In contrast, G,, mKNA increased 20% (P < .01) in striatum and 97% (P < .Ol), in hypothalamus. In hippocampus the changes were reversed: PPE mRNA increased (55%, P < .05) and G,, mRNA decreased (33%, P < .01). Frontal cortex exhibited a small decrease in PPE (11.5 % , P < .05) without any change on G,, or DYN mRNA levels. These reciprocal alterations suggest an opposing mode of regulation of G,, and PPE/DYN gene expression in morphine tolerant animals.