morphine-6-glucuronide and Hyperphagia

Opiate drugs such as morphine stimulate food intake in rats. The morphine metabolite, morphine-6beta-glucuronide (M6G), is more active than morphine in analgesic assays, and appears to act through distinct receptors. Thus, although morphine analgesia is decreased by antisense oligodeoxynucleotides (AS ODNs) targeting exons 1 and 4 of the MOR-1 clone, M6G analgesia is reduced by probes targeting exons 2 and 3 of the MOR-1 clone. Our study examined whether central administration of M6G increased food intake in rats, and characterized this response using either selective mu, kappa1, delta1 and delta2 antagonists, or antisense directed against the various cloned opioid receptors. Central M6G (10-1000 ng) significantly and dose-dependently increased intake after 4 hr. Whereas mu antagonism with betaFNA significantly and dose-dependently reduced M6G-induced hyperphagia, equimolar doses of delta1, delta2, and kappa1 antagonists were ineffective. AS ODNs directed against either exons 2 or 3 of the MOR-1 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-induced hyperphagia. Whereas M6G-induced hyperphagia was insensitive to antisense probes directed against the DOR-1, KOR-1 and KOR-3/ORL1 clones, these probes respectively reduced hyperphagia induced by deltorphin II, U50488H and nociceptin. Although pharmacological data indicate that M6G-induced hyperphagia acts through mu receptors, antisense data imply that the hyperphagic actions of M6G are mediated by a receptor distinct from traditional mu agonists, either as an alternative splice variant of the MOR-1 clone or a distinct gene.

Topics: Animals; Base Sequence; Hyperphagia; Morphine Derivatives; Narcotic Antagonists; Oligonucleotides, Antisense; Opioid Peptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid