Theophylline blocks ethanol withdrawal-induced hyperalgesia

Aims: This study examined the effects of theophylline on the hyperalgesia produced by ethanol withdrawal using a radiant heat tail-flick assay. Methods: Chronic effects of ethanol were tested in four groups of rats which received 10 days exposure to a liquid diet {ethanol alone or with theophylline [0.5 and 1.0 mg/kg, twice daily, intraperitoneally (i.p.)], and dextrin control diet}. Ethanol withdrawal was tested 12 h after removal of the liquid diet. Effects of cumulative doses of the non-selective adenosine agonist 2-chloroadenosine (2-CADO; 0.6-10 mg/kg, i.p.) were tested during withdrawal in the ethanol-treated groups. Results: Chronic exposure to ethanol produced antinociception, and hyperalgesia was seen during withdrawal. Subchronic administration of theophylline (0.5-1.0 mg/kg, twice daily, i.p.) dose-dependently prevented the ethanol-withdrawal-induced hyperalgesia. During ethanol withdrawal, 2-CADO was less potent than when given to non-dependent rats and this effect was prevented by subchronic administration of theophylline (1.0 mg/kg). Conclusions: These findings provide behavioural evidence in agreement with earlier work on the role of adenosine in the development of ethanol tolerance and withdrawal, and suggest that adenosine receptors play an important role in the development of hyperalgesia during ethanol withdrawal.