Pre-incubated cortical brain slices from adult male Sprague Dawley rats when challenged by exogenous norepinephrine (NE) exhibited a dose-dependent increase in the level of endogenous cyclic 3',5' adenosine monophosphate (cyclic AMP), with the maximal response elicited at 50 microM NE concentration. The administration of 50 mg/kg sub-cutaneous (Sub-Q) morphine 5 minutes before sacrifice significantly increased the responsiveness of the brain slices to the NE-induced cyclic AMP response at 0.5, 5.0, and 50.0 microM NE. Sustained administration of morphine from the subcutaneously implanted morphine pellet (75 mg morphine base) attenuated the potentiated cyclic AMP response to NE in the brain slices of the rats exposed to a single challenge dose of 50 mg/kg (Sub-Q) morphine 5 minutes before sacrifice. This tolerance or attenuated response 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 challenge 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 the brain slices, 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.