Dynorphin A_1–17-Induced Feeding: Pharmacological Characterization Using Selective Opioid Antagonists and Antisense Probes in Rats

Abstract

Ventricular administration of the opioid dynorphin A 1-17 induces feeding in rats. Because its pharmacological characterization has not been fully identified, the present study examined whether a dose-response range of general and selective opioid antagonists as well as antisense oligodeoxynucleotide (AS ODN) opioid probes altered daytime feeding over a 4-h time course elicited by dynorphin. Dynorphin-induced feeding was significantly reduced by a wide range of doses (5-80 nmol i.c.v.) of the selective 1 -opioid antagonist nor-binaltorphamine. Correspondingly, AS ODN probes directed against either exons 1 and 2, but not 3 of the -opioid receptor clone (KOR-1) reduced dynorphin-induced feeding, whereas a missense oligodeoxynucleotide control probe was ineffective. Furthermore, AS ODN probes directed against either exons 1 or 2, but not 3 of the 3 -like opioid receptor clone (KOR-3/ORL-1) also attenuated dynorphin-induced feeding. Although the selective -antagonist ␤-funaltrexamine (20 -80 nmol) reduced dynorphininduced feeding, an AS ODN probe directed only against exon 1 of the -opioid receptor clone was transiently effective. Neither general (naltrexone, 80 nmol) nor ␦ (naltrindole, 80 nmol)-selective opioid antagonists were particularly effective in reducing dynorphin-induced feeding, and an AS ODN probe targeting the individual exons of the ␦-opioid receptor clone failed to significantly reduce dynorphin-induced feeding. These converging antagonist and AS ODN data firmly implicate the 1 -opioid receptor and the KOR-1 and KOR-3/ORL-1 opioid receptor genes in the mediation of dynorphin-induced feeding.The role of the endogenous opioid system in the mediation of ingestive behavior has been well established (for review, see Gosnell and Levine, 1996). Thus, direct microinjections of the endogenous opioid peptides ␤-endorphin (Grandison and Guidotti, 1977) and dynorphin (Morley et al., 1982;Morley and Levine, 1983) stimulate feeding. Subsequently, selective opioid receptor agonists and antagonists were used to elucidate specific opioid receptor mechanisms modulating feeding. Hence, feeding induced by the endogenous opioid peptides has not been previously characterized in terms of receptor pharmacology. Recently, our laboratory (Silva et al., 2001) used general and selective (, ␦, and 1 ) opioid receptor antagonists as well as antisense oligodeoxynucleotide (AS ODN) probes directed against specific exons of the MOR-1, DOR-1, KOR-1, and KOR-3/ORL-1 opioid receptor genes to characterize feeding responses elicited by ␤-endorphin, and found that the -opioid receptor was firmly implicated in the mediation of ␤-endorphin-induced feeding based upon the magnitude of selective -opioid antagonism, and the effectiveness of AS ODN probes directed against either exons 1, 3, or 4 of the MOR-1 opioid receptor clone. The present study used an identical antagonist and AS ODN approach to characterize the pharmacology of the feeding response elicited by the endogenous opioid peptide dynorphin A 1-17 .Dynorphin is derived from ...

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

“…The discrepancies between pharmacological and genetic studies may be related to the shortlived and modest intensity of opioid pharmacological stimulation of feeding (3). In addition, our knowledge of the true in vivo selectivity of ligand-receptor interactions that have been established in vitro remains poor (9,14), and the mode of action of opioid-receptor ligands also relies on the dose, the experimental paradigm (acute versus chronic treatment), and the site of administration (5,14,27). Alternatively, the feeding phenotype of MOR Ϫ/Ϫ mice might reflect the redundancy of brain orexigenic signaling (28) or compensatory brain changes in animals with MOR deleted through their lifetime.…”

“…Pharmacological studies suggest that the and pathways are part of an interconnected brain network and participate in the orexigenic effect of several peptides that regulate food intake (10 -13). However, the interpretation of these data is complicated by our poor knowledge of the in vivo selectivity of ligand-receptor interactions that have been established in vitro (9,14).…”

“…Pharmacological studies suggest that the and pathways are part of an interconnected brain network and participate in the orexigenic effect of several peptides that regulate food intake (10 -13). However, the interpretation of these data is complicated by our poor knowledge of the in vivo selectivity of ligand-receptor interactions that have been established in vitro (9,14).Recent studies conducted in mutant mice null for the opioid receptors have complemented pharmacological approaches and clarified the role of each receptor in nociception, anxiety, and drug abuse (14). To further define the role of the -opioid receptor (MOR) pathway in energy homeostasis, we characterized mice lacking the MOR gene (MOR).…”

“…The need to establish the specific role of the opioid receptors in energy homeostasis has led to studies using putative specific opioid receptor ligands or, more recently, antisense probes directed against specific exons of opioid receptor genes (3,9). Pharmacological studies suggest that the and pathways are part of an interconnected brain network and participate in the orexigenic effect of several peptides that regulate food intake (10 -13).…”

An orexigenic role for μ-opioid receptors in the lateral parabrachial nucleus

“…feeding; hyperphagia; DAMGO; naloxone; CTAP STIMULATING ANY OF THE SUBTYPES of opioid receptors (ORs; , , ␦) or the related orphan receptor for nociceptin increases food intake in mammals (6,24,26,71,77). The orexigenic effects of these treatments are evident particularly in settings using preferred foods for the test diet (e.g., 39, 94, 95), although consumption of standard chow is also enhanced (9, 72).…”