ANTISENSE MAPPING THE MOR-1 OPIOID RECEPTOR - EVIDENCE FOR ALTERNATIVE SPLICING AND A NOVEL MORPHINE-6-BETA-GLUCURONIDE RECEPTOR

Although MOR-1 encodes a mu opioid receptor, its relationship to the p harmacologically defined mu receptor subtypes has been unclear. Antise nse mapping now suggests that these subtypes result from alternative s plicing of MOR-1. Three oligodeoxynucleotide probes targeting exon 1 a nd another oligodeoxynucleotide directed against the coding region of exon 4 block supraspinal morphine analgesia, a mu(1) action, while fiv e of six oligodeoxynucleotides directed against exons 2 and 3 are inac tive. Inhibition of gastrointestinal transit and spinal morphine analg esia, two mu(2) actions, are blocked only by the probe against exon 4 and not by those directed against exon 1. In contrast, the analgesic a ctions of the extraordinarily potent mu drug morphine-6 beta-glucuroni de are blocked by six different antisense oligodeoxynucleotides target ing exons 2 and 3, but not by those acting on exons 1 or 4. These resu lts suggest that the mu(1) and mu(2) receptor subtypes originally defi ned in binding and pharmacological studies result from alternative spl icing of MOR-1 while morphine-6 beta-glucuronide acts through a novel previously unidentified receptor which is yet another MOR-1 splice var iant.