Changes in cortical acetylcholine and gamma-aminobutyric acid outflow during morphine withdrawal involve alpha-1 and alpha-2 receptors.
Naloxone (0.3-9 mumol kg-1), electrical stimulation of locus ceruleus or clonidine at low doses (7.5-112 nmol kg-1) increased the release of acetylcholine from the exposed parietal cortex of freely moving, morphine-tolerant guinea pigs. This increase was not additive and was prevented by prazosin (35.8 nmol kg-1), suggesting the involvement of alpha-1 receptors. At high doses (374 nmol kg-1 or more) clonidine inhibited acetylcholine release through alpha-2 receptors, as it did in naive animals at 7.5 nmol kg-1. Clonidine (374 nmol kg-1) and prazosin (35.8 nmol kg-1) reduced the objective signs of naloxone-precipitated withdrawal. Electrical stimulation of the locus ceruleus or naloxone treatment reduced the release of gamma-aminobutyric acid (GABA) from the exposed parietal cortex of morphine-tolerant guinea pigs. This reduction was not additive and was prevented by idazoxan (84 nmol kg-1), suggesting the involvement of alpha-2 receptors. Clonidine (7.5 nmol kg-1), too, reduced the release of GABA in morphine-tolerant animals. However, when tested jointly with naloxone, clonidine (7.5-112 nmol kg-1) induced alpha-1-mediated facilitation of GABA release (like that elicited in naive animals at 112-374 nmol kg-1) leaving the signs of withdrawal unchanged. This points to the stimulation of alpha-1 receptors highly responsive to this agonist (but not to locus ceruleus stimulation) during naloxone-precipitated withdrawal. In conclusion, chronic morphine treatment modifies the alpha-1- and alpha-2-mediated control of GABA and acetylcholine neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Beani
L
L
Department of Pharmacology, University of Ferrara, Italy.
Tanganelli
S
S
Antonelli
T
T
Simonato
M
M
Spalluto
P
P
Tomasini
C
C
Bianchi
C
C
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D019329:Idazoxan; D008125:Locus Coeruleus / Q000502:physiology; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D009270:Naloxone; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D003000:Clonidine; D000109:Acetylcholine; D011224:Prazosin; D019329:Idazoxan