Effects of systemically administered dynorphin A(1-17) in rhesus monkeys

The effects of i.v. dynorphin A(1-17) and its main nonopioid biotransformat ion fragment, dynorphin A(2-17),were compared in rhesus monkeys with those of the selective kappa-opioid agonist, U69,593, in assays of operant behavi or, thermal antinociception, and neuroendocrine function (prolactin release ). Dynorphin A(1-17) (0.1-3.2 mg/kg i.v.) and U69,593 (0.001-0.032 mg/kg s. c.) decreased rates of schedule-controlled (fixed ratio 20) food-reinforced responding, whereas dynorphin A(2-17) (1-3.2 mg/kg i.v.) was ineffective. Pretreatment studies with the opioid antagonist quadazocine (0.32 mg/kg s.c .) revealed that the operant effects of dynorphin A(1-17) were not mediated by kappa- or mu-opioid receptors. A different profile was observed in the warm water tail withdrawal assay of thermal antinociception, where both dyn orphin A(1-17) and A(2-17) (0.032-3.2 mg/kg i.v., n = 4) were modestly effe ctive in 50 degrees C water, and both were ineffective in 55 degrees C wate r. By comparison, U69,593 (0.032-0.18 mg/kg s.c.) was maximally effective i n 50 degrees C water and partially effective in 55 degrees C. kappa-opioid agonists increase serum levels of prolactin in animals and humans, Dynorphi n A(1-17) (ED50 = 0.0011 mg/kg i.v.), similar to U69,593 (ED50 = 0.0030 mg/ kg i.v.), was very potent in increasing serum prolactin levels in follicula r phase female rhesus monkeys, whereas dynorphin A(2-17) (0.32 mg/kg i.v.) was ineffective. The effects of dynorphin A(1-17) and U69,593 on serum prol actin were both antagonized by quadazocine (0.32 mg/kg s.c.) in a surmounta ble manner, consistent with opioid receptor mediation. The present studies show that serum prolactin levels are a sensitive quantitative endpoint to s tudy the systemic effects of the endogenous opioid peptide, dynorphin A(1-1 7), in primates.