NPY-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats.

The ability of neuropeptide Y to potently stimulate food intake is dependent in part upon the functioning of mu and kappa opioid receptors. The combined use of selective opioid antagonists directed against mu, delta or kappa receptors and antisense probes directed against specific exons of the MOR-1, DOR-1, KOR-1 and KOR-3/ORL-1 opioid receptor genes has been successful in characterizing the precise receptor subpopulations mediating feeding elicited by opioid peptides and agonists as well as homeostatic challenges. The present study examined the dose-dependent (5-80 nmol) cerebroventricular actions of general and selective mu, delta, and kappa1 opioid receptor antagonists together with antisense probes directed against each of the four exons of the MOR-1 opioid receptor gene and each of the three exons of the DOR-1, KOR-1, and KOR-3/ORL-1 opioid receptor genes upon feeding elicited by cerebroventricular NPY (0.47 nmol, 2 ug). NPY-induced feeding was dose-dependently decreased and sometimes eliminated following pretreatment with general, mu, delta, and kappa1 opioid receptor antagonists. Moreover, NPY-induced feeding was significantly and markedly reduced by antisense probes directed against exons 1, 2, and 3 of the MOR-1 gene, exons 1 and 2 of the DOR-1 gene, exons 1, 2, and 3 of the KOR-1 gene, and exon 3 of the KOR-3/ORL-1 gene. Thus, whereas the opioid peptides, beta-endorphin and dynorphin A(1-17) elicit feeding responses that are respectively more dependent upon mu and kappa opioid receptors and their genes, the opioid mediation of NPY-induced feeding appears to involve all three major opioid receptor subtypes in a manner similar to that observed for feeding responses following glucoprivation or lipoprivation.

Feeding induced by food deprivation is differentially reduced by opioid receptor antisense oligodeoxynucleotide probes in rats.

The increases in food intake following 24 h of food deprivation are reduced by systemic and central administration of general opioid antagonists. The use of selective opioid antagonists revealed that mu-selective antagonists were more effective than kappa-selective antagonists in reducing deprivation-induced intake, whereas delta-selective antagonists were minimally effective. Antisense oligodeoxynucleotide (AS ODN) probes directed against different exons of the mu (MOP), delta (DOP), kappa (KOP) and nociceptin (NOP) opioid peptide receptor genes have been able to differentially alter feeding responses elicited by glucoprivation, lipoprivation and by different opioid peptides and receptor agonists. The present study examined whether lateral ventricular administration of AS ODN probes directed against different exons of the MOP, DOP, KOP or NOP opioid receptor genes altered food intake and body weight changes following 24 h of food deprivation in rats. Deprivation-induced feeding was significantly and maximally reduced by an AS ODN probe directed against exon 2, but not exons 1 or 3 of the KOP gene. This response was also significantly though modestly reduced by AS ODN probes directed against exons 2, 3 or 4 of the MOP gene, exon 1 of the DOP gene, or exon 1 of the NOP gene. Recovery of body weight following postdeprivation food reintroduction was significantly reduced by AS ODN probes directed against either exons 2, 3 or 4 of the MOP gene, exons 1 or 2 of the DOP gene, or exons 1, 2 or 3 of the KOP gene. The parallel patterns in the magnitude of alterations in deprivation-induced feeding by delta antagonists and DOP AS ODN probes on one hand, and by kappa antagonists and KOP AS ODN probes on the other, provide converging and complementary evidence for their relative involvement in this response. The modest reductions by MOP AS ODN probes relative to the more potent reductions induced by mu-selective antagonists suggest that the mu receptor-mediated actions upon deprivation-induced feeding may involve recently-identified splice variants or isoforms of the MOP gene.