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J Pharmacol Exp Ther. 1988 Oct;247(1):294-301.

Inversion of the alpha-2 and alpha-1 noradrenergic control of the cortical release of acetylcholine and gamma-aminobutyric acid in morphine-tolerant guinea pigs.

Author information

1
Department of Pharmacology, University of Ferrara, Italy.

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.

PMID:
2845056
[Indexed for MEDLINE]

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