Differential blockade of morphine and morphine-6β-glucuronide analgesia by antisense oligodeoxynucleotides directed against MOR-1 and G-protein α subunits in rats

Abstract

An antisense oligodeoxynucleotide directed against the 5′-untranslated region of MOR-1 blocks the analgesic actions of the μ₁ analgesics morphine and [d-Ala²,d-Leu⁵jenkephalin (DADL) when they are microinjected into the periaqueductal gray. In contrast, morphine-6β-glucuronide (M6G) analgesia is unaffected by this treatment. Antisense oligodeoxynucleotides directed against distinct G_iα subunits also distinguish between morphine and M6G analgesia. A probe targeting G_iα2 blocks morphine analgesia, as previously reported, but is inactive against M6G analgesia. Conversely, an antisense oligodeoxynucleotide against G_iαI inhibits M6G analgesia without affecting morphine analgesia. The antisense oligodeoxynucleotide directed against G₀α is ineffective against both compounds. These results confirm the prior association of G_iα2 with morphine analgesia and strongly suggests that M6G acts through a different opioid receptor, as revealed by its insensitivity towards the MOR-1 antisense probe and differential sensitivity towards G-protein α subunit antisense oligodeoxynucleotides.