Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 352, Issue 5, pp 565–575 | Cite as

Protein kinases in the locus coeruleus and periaqueductal gray matter are involved in the expression of opiate withdrawal

  • Rafael Maldonado
  • Olga Valverde
  • Christiane Garbay
  • Bernard P. Roques
Original Article


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 μg) 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.

Key words

Protein kinases Tyrosine kinase inhibitor Serine/threonine kinase inhibitor Locus coeruleus Periaqueductal gray matter Morphine withdrawal Naloxone 



2-hydroxy-5[N-[2,5-dihydroxyphenyl)methyl]amino]-benzoic acid 3-phenylpropyl ester




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Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Rafael Maldonado
    • 1
  • Olga Valverde
    • 1
  • Christiane Garbay
    • 1
  • Bernard P. Roques
    • 1
  1. 1.Département de Pharmacochimie Moléulaire et Structurale, U266 INSERM, URA D1500 CNRS, UFR des Sciences Pharmaceutiques et BiologiquesUniversité René Descartes, Faculté de Pharmacie, 4Paris Cedex 06France

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