THEOPHYLLINE BLOCKS ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA

Alcohol & Alcoholism Vol. 37, No. 4, pp. 313–317, 2002 THEOPHYLLINE BLOCKS ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA MICHAEL B. GATCH* and MEGHAN SELVIG Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA (Received 8 August 2001; in revised form 19 November 2001; accepted 4 December 2001) Abstract — 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. INTRODUCTION separate mechanisms, as do the findings that a benzodiazepine site antagonist blocks the antinociceptive effects of ethanol, whereas a benzodiazepine site agonist fails to produce antinociception. Ethanol is known to have a direct effect on adenosine release and transport, and tolerance to some of ethanol’s effects is apparently mediated by adenosine (Dar and Clark, 1992; Sapru et al., 1994; Coe et al., 1996). Chronic exposure to ethanol leads to desensitization of receptor-stimulated cAMP production and adenosine transport, which produces tolerance to some effects of ethanol (Nagy et al., 1991; Sapru et al., 1994; Wannamaker and Nagy, 1995; Coe et al., 1996). Behavioural studies are in agreement with these molecular studies, indicating that adenosine receptor antagonists are effective at reversing signs of ethanol intoxication such as the motor incoordination produced by alcohol (Dar and Wooles, 1986; Dar et al., 1987; Clark and Dar, 1988), and adenosine A1 agonists have been found to suppress ethanol withdrawal tremors and seizures in rats (Concas et al., 1994, 1996; Malec et al., 1996). Taken together, these findings suggest that adenosine may play a prominent role in the mediation of the nociceptive effects of ethanol during acute and chronic administration as well as during withdrawal. Chronic administration of theophylline up-regulated adenosine A1 receptors in an in vitro study (Szot et al., 1987). This finding raised the possibility that co-administration of theophylline with ethanol could at least partially counteract the desensitization of adenosine transport, and thereby reduce the severity of ethanol withdrawal. An earlier study reported that subchronic administration of 8-cyclopentyl-1,3-dimethylxanthine (CPT) reduced ethanol withdrawal anxiety (Gatch et al., 1999). The purpose of the present study was to characterize the effects of subchronic theophylline on hyperalgesia during ethanol withdrawal. Because theophylline up-regulated adenosine A1 receptors, it is possible that it might also block ethanol-withdrawal induced hyperalgesia. To test this hypothesis, we administered theophylline (0.5 or 1.0 mg/kg, twice daily) throughout exposure to the ethanol-containing liquid diet, and compared tail-flick latencies during withdrawal to groups which received only the ethanol diet or no ethanol at all (dextrin control). The discomfort that is a central part of ethanol withdrawal may not merely be due to anxiety or other types of cognitive distress, but may reflect an actual increase in sensitivity to painful stimuli. A number of studies have shown that acute administration of ethanol produces modest degrees of analgesia (Jørgensen and Hole, 1981; Pohorecky and Shah, 1987). Chronic administration of ethanol produces antinociception followed by the development of tolerance to its antinociceptive effects (Malec et al., 1987; Gatch, 1999; Gatch and Lal, 1999). Research from our own laboratory has shown that chronic exposure to ethanol (6.5% w/v) in a liquid diet for 10 days resulted in antinociception from day 2 to day 6, development of tolerance on days 8–10, and marked hyperalgesia 6–12 h after withdrawal of ethanol (Gatch, 1999; Gatch and Lal, 1999). In a subsequent study, the benzodiazepine site antagonist flumazenil blocked the antinociception produced by acute doses of ethanol. Further, when flumazenil (10 mg/kg, twice daily) was given chronically during exposure to the ethanolcontaining liquid diet, the antinociceptive effects of ethanol were blocked, and hyperalgesia did not develop during withdrawal (Gatch, 1999). Both ethanol and diazepam reversed the hyperalgesia seen during ethanol withdrawal, although ethanol did not produce any further antinociceptive effects (Gatch, 1999). However, these anti-hyperalgesic effects were not reversed by flumazenil (10–50 mg/kg). That ethanol should reverse the hyperalgesia, while the rats still show tolerance to its antinociceptive effects, suggests that the antinociceptive and hyperalgesic effects might be mediated by different receptors. Alternatively, lower doses of drugs are needed to reverse hyperalgesia (Negus et al., 1995), and ethanol may retain enough effect to reverse the hyperalgesia without producing antinociception. The failure of flumazenil to block the antihyperalgesic effects of ethanol and diazepam adds further support to the possibility of *Author to whom correspondence should be addressed. 313 © 2002 Medical Council on Alcohol 314 M. B. GATCH and M. SELVIG In addition, there is molecular evidence of desensitization to adenosine agonists during ethanol withdrawal (Nagy et al., 1991; Sapru et al., 1994; Wannamaker and Nagy, 1995). To provide behavioural evidence that subchronic administration of theophylline can prevent the ethanol-induced desensitization to adenosine agonists, 2-chloroadenosine (2-CADO, a nonselective adenosine agonist) was administered to non-dependent rats, and during ethanol withdrawal in groups which received a liquid diet containing ethanol alone, or ethanol and twicedaily injections of theophylline. Our hypothesis was that 2-CADO would be less potent in rats receiving the liquid diet than in those receiving the dextrin control, and that coadministration of theophyl (...truncated)