EFFECTS OF ACUTE AND CONTINUOUS ADMINISTRATION OF MORPHINE ON THE CYCLIC-AMP RESPONSE INDUCED BY NOREPINEPHRINE IN RAT-BRAIN SLICES

Pre-incubated cortical brain slices from adult male Sprague Dawley rat s when challenged by exogenous norepinephrine (NE) exhibited a dose-de pendent increase in the level of endogenous cyclic 3', 5' adenosine mo nophosphate (cyclic AMP), with the maximal response elicited at 50 mu M NE concentration. The administration of 50 mg/kg sub-cutaneous(Sub-Q ) morphine 5 minutes before sacrifice significantly increased the resp onsiveness of the brain slices to the NE-induced cyclic AMP response a t 0.5, 5.0, and 50.0 mu M NE. Sustained administration of morphine fro m the subcutaneously implanted morphine pellet (75 mg morphine base) a ttenuated the potentiated cyclic AMP response to NE in the brain slice s of the rats exposed to a single challenge dose of 50 mg/kg (Sub-Q) m orphine 5 minutes before sacrifice. This tolerance or attenuated respo nse is first observed 24 hours after morphine pellet implantation with maximal tolerance observed at 48 hours after the pellet implantation. A complete reversal of attenuated NE-induced cyclic AMP response was observed when the 3 day morphine implanted rats were injected with a c hallenge dose of naloxone (4 mg/kg, Sub-Q) at 10 minutes prior to the acute administration of 50 mg/kg Sub-Q injection of morphine 5 minutes before sacrifice. These results suggest that both acute and prolonged administration of morphine alters NE-induced cyclic AMP response of t he brain dices, and that naloxone, an opioid antagonist, reverses this response. This is perhaps due to morphine-induced alterations in the availability of NE in the CNS.