MORPHINE-6-BETA-GLUCURONIDE-INDUCED HYPERPHAGIA - CHARACTERIZATION OFOPIOID ACTION BY SELECTIVE ANTAGONISTS AND ANTISENSE MAPPING IN RATS

Opiate drugs such as morphine stimulate food intake in rats. The morph ine metabolite, morphine-6 beta-glucuronide (M6G), is more active than morphine in analgesic assays, and appears to act through distinct rec eptors. Thus, although morphine analgesia is decreased by antisense ol igodeoxynucleotides (AS ODNs) targeting exons 1 and 4 of the MOR-I clo ne, M6G analgesia is reduced by probes targeting exons 2 and 3 of the MOR-I clone. Our study examined whether central administration of M6G increased food intake in rats, and characterized this response using e ither selective mu, kappa(1), delta(1) and delta(2) antagonists, or an tisense directed against the various cloned opioid receptors. Central M6G (10-1000 ng) significantly and dose-dependently increased intake a fter 4 hr. Whereas mu antagonism with beta FNA significantly and dose- dependently reduced M6G-induced hyperphagia, equimolar doses of delta( 1), delta(2), and kappa(1) antagonists were ineffective. AS ODNs direc ted against either exons 2 or 3 of the MOR-I clone blocked M6G-induced hyperphagia, whereas either AS ODNs directed against exons 1 or 4, or a MS ODN directed against exon 2 were ineffective. In contrast, an AS ODN probe directed against exon 1, but not exon 2, of the MOR-1 clone reduced morphine-induced hyperphagia, an effect identical to DAMGO-in duced hyperphagia. Whereas M6G-induced hyperphagia was insensitive to antisense probes directed against the DOR-1, KOR-1 and KOR-3/ORL1 clon es, these probes respectively reduced hyperphagia induced by deltorphi n II, U50488H and nociceptin. Although pharmacological data indicate t hat M6G-induced hyperphagia acts through mu receptors, antisense data imply that the hyperphagic actions of M6G are mediated by a receptor d istinct from traditional mu agonists, either as an alternative splice variant of the MOR-1 clone or a distinct gene.