Naloxone benzoylhydrazone, a κ₃ opioid agonist, stimulates food intake in rats

Naloxone benzoylhydrazone (NalBzoH) is a selective, short-acting agonist at the κ₃ opioid receptor and a slowly dissociating potent antagonist at the mu opioid receptor. Given the important role of κ receptors in the opioid control of food intake, the present study examined the central and peripheral effects of NalBzoH upon food intake. Central administration of NalBzoH (1-20 μg, i.c.v.) significantly increased food intake for up to 12 h, but failed to alter intake or body weight after 24 or 48 . The 12 h duration of NalBzoH-mediated effects may be due to either persistent κ₃ receptor occupancy, and/or activation of an ingestive system which maintains its activity. Peripheral administration of NalBzoH (20 mg/kg, s.c.) significantly increased food intake for up to 1 h. To distinguish κ₁ (U50,488H) and κ₃ (NalBzoH) hyperphagic effects, these agonist effects were compared following pretreatment with either naltrexone or the κ₁ antagonist, nor-binaltorphamine (Nor-BNI). Whereas naltrexone significantly reduced both U50,448H and NalBzoH hyperphagia, Nor-BNI blocked U50,448H, but not NalBzoH hyperphagia. These data indicate a distinct role for the κ₃ receptor in ingestive behavior separable from thatof κ₁ effects.