Protective effect of cyclooxygenase-2 (COX-2) inhibitors but not non-selective cyclooxygenase (COX)-inhibitors on ethanol withdrawal-induced behavioural changes.

Cyclooxygenase (COX) is reported to play a significant role in neurodegeneration. Recent studies have shown that chronic ethanol administration up-regulates cyclooxygenase expression. In the present study we examined the effect of nimesulide (a preferential COX-2 inhibitor), rofecoxib (a highly selective COX-2 inhibitor) or naproxen (a non-selective COX-inhibitor displaying high affinity towards the COX-1 isoenzyme) on alcohol-induced withdrawal symptoms. Mice were made physically dependent on alcohol by the chronic administration of ethanol (2 g/kg of 10% v/v), intragastrically, twice on day 1 and then once-daily on successive days for a total of 7 days. Nimesulide [2.5 mg/kg, intraperitoneally (i.p.)], rofecoxib (2 mg/kg, i.p.) or naproxen (7 mg/kg, i.p.) were administered daily for 7 days before administering alcohol intragastrically. After 24 hours of the last alcohol administration, the treatments were reversed and the mice were tested for withdrawal, so that the animals that had received COX-inhibitors followed 30 minutes later by ethanol on days 1-7 were challenged with saline. Similarly, the animals which received saline followed 30 minutes later by ethanol received only saline. Behavioural analysis revealed hyperlocomotor activity, increased anxious response and increased hyperalgesia in mice. Also, alcohol withdrawal decreased the threshold for Pentylenetetrazole-(PTZ)-induced convulsions. Pretreatment with COX-inhibitors rofecoxib (2 mg/kg, i.p.) or nimesulide (2.5 mg/kg, i.p.) displayed significant protection against ethanol-induced withdrawal symptoms, while naproxen (7 mg/kg, i.p.) was not effective in reversing alcohol-induced withdrawal symptoms. The results of the present study suggest strongly the possible role of cyclooxygenases, particularly COX-2 inhibitors, on ethanol-induced withdrawal symptoms and the potential use of COX-2 inhibitors in their prevention and treatment.