Extraneuronal noradrenaline in the prefrontal cortex of morphine-dependent rats: tolerance and withdrawal mechanisms.

The changes in extracellular concentrations of noradrenaline (NA) in the prefrontal cortex of morphine-dependent rats were studied by microdialysis following an acute morphine challenge and during naloxone-precipitated withdrawal. Animals were implanted with morphine- or placebo-containing pellets for 5 days. In control rats a challenge dose of morphine (5 mg/kg s.c.) induced a maximum decrease in NA output of about 45% of pre-drug levels. In contrast, morphine challenge had no effect on extraneuronal NA concentrations in morphine-implanted animals. In control animals, naloxone (2 mg/kg i.p.) produced no behavioral effect nor changed NA levels. However, in morphine-dependent animals naloxone suddenly increased extraneuronal NA by 175% of baseline dialysate levels in the first sample after the injection and precipitated a morphine-withdrawal symptomatology that paralleled the changes in NA output. Thus, chronic morphine treatment in rats results in the development of tolerance to the acute inhibitory effect of morphine on extraneuronal NA and is associated with a stimulation of prefrontocortical NA output during naloxone-precipitated withdrawal.