PROTEIN-KINASES IN THE LOCUS-COERULEUS AND PERIAQUEDUCTAL GRAY-MATTERARE INVOLVED IN THE EXPRESSION OF OPIATE WITHDRAWAL

The aim of this study was to evaluate the role played in the behaviora l expression of morphine withdrawal syndrome by protein kinases in the locus coeruleus and the periaqueductal gray matter. Two different fam ilies of specific protein kinases have been investigated: serine/threo nine and tyrosine kinases. Rats were implanted with cannulas into both the lateral ventricle and the locus coeruleus or the periaqueductal g ray matter. Physical dependence was induced by chronic peripheral admi nistration of morphine (from 7 to 30 mg/kg) and withdrawal syndrome wa s precipitated by injection of naloxone (2 mu g) into the lateral vent ricle. 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 mo rphine withdrawal behavior. Signs related to the motor component of ab stinence, such as jumping, rearing, and hyperactivity, were the most s everely reduced. However, this effect was not dose-dependent, and the response was almost the same with all the doses used. A similar attenu ation was observed after the injection of H7 (1, 3, and 10 nmol per si de) 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 tyrosin e kinase inhibitor y-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 th e withdrawal syndrome behavior, except on teeth chattering. These resu lts suggest that, in the locus coeruleus and in the periaqueductal gra y matter, serine/threonine kinases are implicated in the behavioral ex pression of morphine abstinence. In these brain structures, tyrosine k inases appear not to be involved.