DIFFERENTIAL BLOCKADE OF MORPHINE AND MORPHINE-6-BETA-GLUCURONIDE ANALGESIA BY ANTISENSE OLIGODEOXYNUCLEOTIDES DIRECTED AGAINST MOR-1 AND G-PROTEIN ALPHA-SUBUNITS IN RATS

An antisense oligodeoxynucleotide directed against the 5'-untranslated region of MOR-l blocks the analgesic actions of the mu(1) analgesics morphine and [D-Ala(2),D-Leu(5)]enkephalin (DADL) when they are microinjected into the periaqueductal gray. In contrast, morphine-6 beta-glucuronide (M6G) analgesia is unaffected by this treatment. Antisense oligodeoxynucleotides directed against distinct G(1) alpha subunits also distinguish between morphine and M6G analgesia. A probe targeting G(1) alpha 2 blocks morphine analgesia, as previously reported, but is inactive against M6G analgesia. Conversely, an antisense oligodeoxynucleotide against G(1) alpha 1 inhibits M6G analgesia without affecting morphine analgesia. The antisense oligodeoxynucleotide directed against G(0) alpha is ineffective against both compounds. These results confirm the prior association of G(1) alpha 2 with morphine analgesia and strongly suggests that M6G acts through a different opioid receptor, as revealed by its insensitivity towards the MOR-I antisense probe and differential sensitivity towards G-protein alpha subunit antisense oligodeoxynucleotides.