Prior research has indicated that tolerance develops to the antinociceptive effects of ethanol and continues even during withdrawal. Three potential pharmacological mechanisms for this tolerance are examined, using nitrendipine (L-type calcium channel blocker), theophylline (adenosine A1/A2 antagonist) and flumazenil (benzodiazepine antagonist). Rats received 10 days of exposure to an ethanol-containing liquid diet (6.5% w/v). A radiant heat tail-flick assay was used to assess hyperalgesia at 12 h after removal of the liquid diet, as well as tolerance to the effects of cumulative doses of ethanol (0.5-2 g/kg). Co-administration of flumazenil (10 mg/kg, i.p., b.i.d.), nitrendipine (5 mg/kg, i.p., b.i.d.) or theophylline (1 mg/kg, i.p., b.i.d.) with chronic ethanol prevented development of the hyperalgesia produced by ethanol withdrawal, but only theophylline reduced tolerance to the antinociceptive effects of ethanol administered during ethanol withdrawal. In contrast, when administered during ethanol withdrawal, theophylline (1-10 mg/kg) blocked the anti-hyperalgesic effects of ethanol during ethanol withdrawal, whereas nitrendipine (5-25 mg/kg) enabled ethanol to produce levels of antinociception comparable to non-dependent rats. These findings indicate that L-type calcium channels and adenosine receptors play important, but differing roles in the development of hyperalgesia during withdrawal, and to tolerance to the antinociceptive effects of ethanol.