Dual effect of cAMP agonist on ameliorative function of PKA inhibitor in morphine‐dependent mice

Abstract

The present study shows interactive effects of bucladesine (db-cAMP) as a cyclic adenosine monophosphate (cAMP) agonist and H-89 as a protein kinase A (PKA) inhibitor on naloxone-induced withdrawal signs in morphine-dependent mice. Animals were treated subcutaneously with morphine thrice daily with doses progressively increased from 50 to 125mg/kg. A last dose of morphine (50mg/kg) was administered on the 4thday. Several withdrawal signs were precipitated by intraperitoneal (i.p.) administration of naloxone (5mg/kg). Different doses of bucladesine (50, 100, 200nm/mouse) and H-89 (0.05, 0.5, 1, 5mg/kg) were administered (i.p.) 60min before naloxone injection. In combination groups, bucladesine was injected 15min before H-89 injection. Single administration of H-89 (0.5, 1, 5mg/kg) and bucladesine (50, 100nm/mouse) significantly attenuated prominent behavioral signs of morphine withdrawal. Lower doses of bucladesine (50, 100nm/mouse) in combination with H-89 (0.05mg/kg) increased the inhibitory effects of H-89 on withdrawal signs while in high dose (200nm/mouse) decreased the ameliorative function of H-89 (0.05mg/kg) in morphine-dependent animals. It is concluded that H-89 and bucladesine could affect morphine withdrawal syndrome via possible interaction with cyclic nucleotide messengering systems, protein kinase A signaling pathways, and modified related neurotransmitters.