Vol. 301, Issue 2, 513-518, May 2002

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

Robert M. Silva, Henya C. Grossman, Maria M. Hadjimarkou, Grace C. Rossi , Gavril W. Pasternak and Richard J. Bodnar

Department of Psychology and Neuropsychology Doctoral Sub-Program, City University of New York, Flushing, New York (R.M.S., H.C.G., M.M.H., R.J.B.); The George C. Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (G.C.R., G.W.P.); and Department of Psychology, CW Post College, Long Island University, Brookville, New York (G.C.R.)

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 µ-antagonist -funaltrexamine (20-80 nmol) reduced dynorphin-induced feeding, an AS ODN probe directed only against exon 1 of the µ-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.