Abstract

Opiate drugs such as morphine stimulate food intake in rats. The morphine metabolite, morphine-6β-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 delta₂antagonists, 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 βFNA significantly and dose-dependently reduced M6G-induced hyperphagia, equimolar doses of delta₁,delta₂, and kappa₁antagonists 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.