Effects of Glycogen Synthase Kinase 3β and Cyclin-Dependent Kinase 5 Inhibitors on Morphine-Induced Analgesia and Tolerance in Rats

• DOI: 10.1124/jpet.106.107581
• Publication Date: 2006-08-11T00:44:18Z
• Authors: Jan Rodriguez Par...; Ilona Obara; Agnieszka Wawrzcz...; Wioletta Makuch; Barbara Przewlocka; Ryszard Przewlocki
• Keywords: Drug tolerance

Repeated administration of morphine is associated with the development tolerance, yet mechanism underlying this phenomenon still poorly understood. Recent evidence implicating glycogen synthase kinase 3 (GSK3) in opioid receptor signaling pathways has prompted us to investigate its role tolerance. Administration 10 mg/kg i.p. Wistar rats twice daily for 8 days resulted complete tolerance analgesic effects as measured by tail-flick test. When injections were preceded intrathecal (i.t.) either an inhibitor GSK3 [(3-(2,4-dichlorophenyl)-4-(1-methyl-1<i>H</i>-indol-3-yl)-1<i>H</i>-pyrrole-2,5-dione (SB216763) or 6-bromoindirubin-3′oxime] cyclin-dependent (Cdk), roscovitine, analgesia was completely abolished. In addition, a single i.t. injection able restore dose-dependent manner effect morphine-tolerant rats. None inhibitors doses used present study had their own nor on potency morphine. caused increase abundance GSK-3β phosphorylated at Ser⁹ dorsal lumbar part spinal cord that chronically treated Furthermore, reversal always increased phospho-GSK3β. conclusion, our data indicate chronic treatment activates highly efficient pathway means which Cdk5 regulates GSK3β activity.