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.
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.
Beani
L
L
Department of Pharmacology, University of Ferrara, Italy.
Bianchi
C
C
Tanganelli
S
S
Antonelli
T
T
Simonato
M
M
Rando
S
S
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004361:Drug Tolerance; D005260:Female; D006168:Guinea Pigs; D019329:Idazoxan; D008125:Locus Coeruleus / Q000502:physiology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009638:Norepinephrine / Q000502:physiology*; D011224:Prazosin / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D003000:Clonidine; D000109:Acetylcholine; D009638:Norepinephrine; D011224:Prazosin; D019329:Idazoxan