Protein Kinases in the Rat Nucleus Accumbens are Involved in the Aversive Component of Opiate Withdrawal

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Abstract
The specific participation of protein kinases in the expression of the somatic signs of morphine withdrawal has been previously demonstrated, suggesting that changes in intracellular signalling systems are involved in opioid addiction. In the present study, the involvement of protein kinases in the aversive/dysphoric effects of morphine abstinence has been investigated in the nucleus accumbens, because of the critical role played by the mesolimbic system in the rewarding effects of opioids. Rats were chronically treated with morphine, twice a day for 5 days, with doses progressively increased from 5 to 30 mg/kg (i‐p.). In addition, microinjections into the nucleus accumbens of the serine‐threonine kinase inhibitors H7 or H8 (1 or 10 nmol per side) or saline once daily were also given, both in control and in morphine‐treated animals. After these chronic treatments, withdrawal syndrome was induced by naloxone administration (0.1 mg/kg, s. c.), and the motivational component of morphine abstinence was studied using the place aversion paradigm. When administered at the highest dose (10 nmol), H7 and H8 strongly reduced the place aversion induced by naloxone in morphine dependent animals. Protein kinase inhibitors did not induce significant behavioural responses in non‐dependent animals. Chronic morphine treatment induced a selective up‐regulation of adenylate cyclase activity in the amygdala, without affecting other brain regions. The morphine‐increased adenylate cyclase activity in amygdala was reversed by the chronic intra‐accumbens microinjection of H7 or H8. These results suggest that serine‐threonine kinases in the nucleus accumbens play an important role in the emotional/dysphoric properties which characterize opiate withdrawal.