Protein kinases in the locus coeruleus and periaqueductal gray matter are involved in the expression of opiate withdrawal.
The aim of this study was to evaluate the role played in the behavioral expression of morphine withdrawal syndrome by protein kinases in the locus coeruleus and the periaqueductal gray matter. Two different families of specific protein kinases have been investigated: serine/threonine and tyrosine kinases. Rats were implanted with cannulas into both the lateral ventricle and the locus coeruleus or the periaqueductal gray matter. Physical dependence was induced by chronic peripheral administration of morphine (from 7 to 30 mg/kg) and withdrawal syndrome was precipitated by injection of naloxone (2 micrograms) into the lateral ventricle. The administration of the serine/threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, H7 (1, 3, 10, and 30 nmol per side) into the locus coeruleus induced a strong attenuation of morphine withdrawal behavior. Signs related to the motor component of abstinence, such as jumping, rearing, and hyperactivity, were the most severely reduced. However, this effect was not dose-dependent, and the response was almost the same with all the doses used. A similar attenuation was observed after the injection of H7 (1, 3, and 10 nmol per side) into the periaqueductal gray matter, but in this case motor signs were less strongly reduced and a larger number of signs were modified, mainly when using the highest dose. The administration of the tyrosine kinase inhibitor 2-hydroxy-5-[N(2,5-dihydroxyphenyl)methyl]amino]-benzoic acid 3-phenylpropyl ester, KB23 (0.3, 1, and 3 nmol per side) into the locus coeruleus or the periaqueductal gray matter had no effect on the withdrawal syndrome behavior, except on teeth chattering. These results suggest that in the locus coeruleus and in the periaqueductal gray matter, serine/threonine kinases are implicated in the behavioral expression of morphine abstinence. In these brain structures, tyrosine kinases appear not to be involved.
Maldonado
R
R
Département of Pharmacochimie Moléculaire et Structurale, U266 INSERM, URA D1500 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Faculté de Pharmacie, Paris, France.
Valverde
O
O
Garbay
C
C
Roques
B P
BP
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008125:Locus Coeruleus / Q000201:enzymology*; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000008:administration & dosage; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome
D000636:Aminosalicylic Acids; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C098612:KB 23; D010879:Piperazines; D009270:Naloxone; D009020:Morphine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases