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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Animals
  • Cerebral Cortex / metabolism*
  • Clonidine / pharmacology
  • Dioxanes / pharmacology
  • Drug Tolerance
  • Female
  • Guinea Pigs
  • Idazoxan
  • Locus Coeruleus / physiology
  • Male
  • Morphine / pharmacology*
  • Norepinephrine / physiology*
  • Prazosin / pharmacology
  • Receptors, Adrenergic, alpha / physiology*
  • gamma-Aminobutyric Acid / metabolism*


  • Dioxanes
  • Receptors, Adrenergic, alpha
  • gamma-Aminobutyric Acid
  • Morphine
  • Clonidine
  • Acetylcholine
  • Norepinephrine
  • Prazosin
  • Idazoxan