Lack of cyclic AMP-specific phosphodiesterase 4 activation during naloxone-precipitated morphine withdrawal in rats.
Intracellular cyclic AMP regulation systems play an important role in the mechanisms of morphine dependence and withdrawal. In the present study, to clarify the involvement of phosphodiesterase (PDE) 4, degradation enzyme of cyclic AMP in morphine dependence and withdrawal we investigated the activities of PDE4 after naloxone-precipitation in single morphine treatment and repeated morphine treatment (morphine-dependence) rats. Naloxone (5 mg/kg, s.c.) challenge caused a significant withdrawal signs such as jumping in morphine-dependent rats following repeated treatment with morphine (4, 8, 12, and 16 mg/kg, twice a day for 4 days), but not in single morphine-treated rats (16 mg/kg, single). Naloxone challenge caused an increase in PDE4 activities in the brain of rats treated with single morphine in connection with the elevation of brain cyclic AMP. In contrast, increase in the PDE4 activities was not caused by naloxone challenge in all brain regions of morphine-dependent rats, although brain cyclic AMP was significantly increased. These results suggest that the lack of PDE4 activation leading to remarkable elevation of cyclic AMP is involved in naloxone-precipitated morphine withdrawal symptoms.
Kimura
Megumi
M
Department of Drug Safety Evaluation, Developmental Research Laboratories, Shionogi and Co. Ltd., Toyonaka, Osaka, Japan.
Tokumura
Miwa
M
Itoh
Tetsuji
T
Inoue
Osamu
O
Abe
Kohji
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004789:Enzyme Activation; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000493:pharmacokinetics; D013375:Substance Withdrawal Syndrome / Q000201:enzymology*
D009270:Naloxone; D009020:Morphine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram