Abstract

In normal guinea pigs the adrenergic agonists clonidine and norepinephrine are known to inhibit directly the cortical outflow of acetylcholine (ACh) through alpha-2 receptors and to increase the cortical outflow of gamma-aminobutyric acid (GABA) through alpha-1 receptors. GABA, in turn, contributes to inhibit ACh through GABAA receptors. This scheme is changed drastically by morphine tolerance. In morphine-tolerant guinea pigs, clonidine at 7.5, 18.7 and 112 nmol/kg i.p. stimulates the cortical release of ACh through alpha-1 receptors. This effect is prevented by prazosin, 35.8 nmol/kg i.p. Clonidine reduces ACh release at high doses only (374 and 1122 nmol/kg i.p.). Furthermore, electrical stimulation of locus ceruleus also gives rise to a prazosin-sensitive increase in ACh release. In addition, locus ceruleus stimulation often causes behavioral activation rather than sedation. In morphine-tolerant guinea pigs, clonidine at 7.5 and 18.7 nmol/kg i.p. reduces GABA efflux through alpha-2 receptors, as the drug effect is prevented by idazoxan, 84 nmol/kg i.p. Clonidine increases GABA efflux at high doses only (112 and 374 nmol/kg i.p.). Locus ceruleus stimulation also gives rise to an idazoxan-sensitive reduction in GABA outflow. This new condition, evident after 7 days of morphine treatment, can be defined as inversion of the physiological norepinephrine control over ACh and GABA outflow and can represent a major part of the neurochemical derangement associated with opioid tolerance.