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 September 2001; accepted 4 December 2001


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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, 1981Go; Pohorecky and Shah, 1987Go). Chronic administration of ethanol produces antinociception followed by the development of tolerance to its antinociceptive effects (Malec et al., 1987Go; Gatch, 1999Go; Gatch and Lal, 1999Go).

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, 1999Go; Gatch and Lal, 1999Go). 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 ethanol-containing liquid diet, the antinociceptive effects of ethanol were blocked, and hyperalgesia did not develop during withdrawal (Gatch, 1999Go).

Both ethanol and diazepam reversed the hyperalgesia seen during ethanol withdrawal, although ethanol did not produce any further antinociceptive effects (Gatch, 1999Go). 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., 1995Go), 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 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, 1992Go; Sapru et al., 1994Go; Coe et al., 1996Go). 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., 1991Go; Sapru et al., 1994Go; Wannamaker and Nagy, 1995Go; Coe et al., 1996Go). 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, 1986Go; Dar et al., 1987Go; Clark and Dar, 1988Go), and adenosine A1 agonists have been found to suppress ethanol withdrawal tremors and seizures in rats (Concas et al., 1994Go, 1996Go; Malec et al., 1996Go). 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., 1987Go). 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., 1999Go). 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).

In addition, there is molecular evidence of desensitization to adenosine agonists during ethanol withdrawal (Nagy et al., 1991Go; Sapru et al., 1994Go; Wannamaker and Nagy, 1995Go). To provide behavioural evidence that subchronic administration of theophylline can prevent the ethanol-induced desensitization to adenosine agonists, 2-chloroadenosine (2-CADO, a non-selective 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 twice-daily 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 co-administration of theophylline with the ethanol diet would reverse this effect.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Male Long–Evans rats obtained from Harlan–Sprague (Indianapolis, IN, USA) were used in the experiments. Rats were ~90 days old at the start of experiments. All rats were housed individually and maintained on a 12 h:12 h light/dark cycle (lights on at 07.00). Rats had free access to water and 22 g/day of food, except when liquid diet was administered. All housing and procedures were in accordance with the guidelines of the Institute of Laboratory Animal Resources, National Research Council (Institute of Laboratory Animal Resources, 1996Go) and were approved by the University of North Texas Health Science Center Animal Care and Use Committee.

Ethanol administration and withdrawal
During chronic ethanol/withdrawal experiments, rats received a nutritionally balanced liquid diet (100 ml) containing 6.5% (w/v) ethanol each morning at 08.00 for 10 days. On the last day of ethanol administration, the liquid diet was removed and the rats were gavaged with a dose of ethanol of 3 g/kg in 10 ml of the liquid diet to standardize the starting time of ethanol withdrawal. Diet control animals were fed liquid diet with dextrin isocalorically substituted for ethanol (Lal et al., 1988Go), and were gavaged with 10 ml of the dextrin diet on day 10. Rats had free access to water and 22 g/day of food once the liquid diet was removed.

Nociception assay
A radiant heat tail-flick assay was used to test changes in nociception. The lower third of the tail is laid over a photocell and exposed to a focused beam of light for a limited period of time, typically no more than 10–20 s. When the subject flicks its tail, the light beam activates the photocell, closing a switch which turns off the heat source. An EMDIE TF-6 radiant heat tail-flick analgesiometer was used at two temperature settings, a low setting at which rats ordinarily do not remove their tails to act as a control for increased agitation and motor activity during withdrawal, and a higher setting to test for the antinociceptive effects of ethanol. A maximum cut-off time of 20 s was used. Each setting was measured on each trial. The order of presentation of intensities was alternated across trials. All experiments were begun between 07.30 and 08.30.

Experimental design
Chronic tests. Tail-flick latencies from the low and medium settings were assessed on day 0 (baseline) and at 12 h after withdrawal of ethanol. During each test session, two measurements were taken, one every 15 min. Separate groups of 12 rats received either dextrin control diet, ethanol alone, ethanol and twice daily injections of theophylline (0.5 or 1.0 mg/kg). Injections were given at 08.00 (immediately after receiving fresh liquid diet and after testing) and at 20.00. The last injection was given on the morning of day 10, i.e. 24 h before testing. A total of 48 rats was used. Immediately before testing, animals were rated for withdrawal signs using a scale (Table 1Go) adapted for rats based on the Goldstein scale for mice (Goldstein, 1972Go).


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Table 1. Ethanol withdrawal signs and scores
 
Acute tests. During withdrawal, cumulative dose–effect curves for 2-CADO (0.6–10) were determined in the groups which received ethanol alone and ethanol in combination with theophylline (1.0 mg/kg, twice daily). Cumulative dosing test sessions consisted of multiple cycles. At the beginning of each test session, tail-flick latencies from both settings were determined during withdrawal. Subsequently, a dose of drug was administered at the beginning of each 30 min cycle. Fifteen minutes after each injection, tail-flick latencies were recorded from the low and high settings as described above. Each dose of 2-CADO doubled the cumulative amount. Cumulative dosing was used because in pilot studies, 2-CADO produced comparable results whether cumulative or single-dose methods were used.

Data analysis
To control for differences in baselines between groups in the 2-CADO dose–effect data, tail-flick latencies were converted to percentage of maximum effect by the formula: (test latency – baseline latency)/(maximum cut-off time – baseline latency) (Walker et al., 1993Go). Only the high intensity data are presented, because latencies at the low intensity were always at the 20 s maximum. Tail-flick latencies, ethanol intakes and ED50 values were analysed by one-way analysis of variance (ANOVA). Post-hoc comparisons were made using Bonferroni's test. Withdrawal scores were analysed by Kruskal–Wallis one-way ANOVA. The criterion for statistical significance was set a priori at P < 0.01.

Drugs
2-Chloroadenosine (2-CADO) was dissolved in saline, and theophylline was administered as a suspension in 3% carboxymethylcellulose. Both drugs were obtained from Research Biochemicals International (Natick, MA, USA). All injections were administered intraperitoneally.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subchronic exposure to theophylline dose-dependently blocked the hyperalgesia produced by ethanol withdrawal (Fig. 1Go). There was a significant difference between the groups [F(3,86) = 12.15, P < 0.001]. In the dextrin control group, tail-flick latencies were higher than in the ethanol-alone group (P < 0.05). Tail-flick latencies in the group which received the larger dose of theophylline (1.0 mg/kg, twice daily) were significantly higher than those in the ethanol-alone group (P < 0.05). Tail-flick latencies in the group which received theophylline (0.5 mg/kg, twice daily) were not significantly different from those in the ethanol-alone group.



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Fig. 1. Effects of subchronically administered theophylline on tail-flick latencies during ethanol withdrawal. Ordinate shows tail flick latency. Abscissa shows experimental group. EtOH, ethanol; Theo, theophylline. Doses of theophylline are in mg/kg, twice daily. *Significantly different from the mean of the ethanol group (Bonferroni's test, P < 0.01). Brackets indicate the SEM (n = 12).

 
As shown in the upper panel of Fig. 2Go, the average consumption of ethanol over the course of the experiment differed significantly between groups [F(2,33) = 12.36, P < 0.001]. Both doses of theophylline increased the amount of ethanol diet consumed (P < 0.05). Moderate levels of withdrawal scores were seen in the ethanol-alone group (lower panel, Fig. 2Go). Withdrawal scores were markedly reduced in the groups which received either dose of theophylline [H = 19.51, P < 0.001].



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Fig. 2. Effects of subchronically administered theophylline on ethanol consumption and withdrawal scores (Goldstein scale) during ethanol withdrawal. Upper panel ordinate shows average ethanol consumption in g/kg/day. Lower panel ordinate shows average withdrawal score. Abscissas show the day of the test. EtOH, ethanol; Theo, theophylline. Doses of theophylline are in mg/kg, twice daily. *Significantly different from the mean of the ethanol group (Bonferroni's test, P < 0.01). Brackets indicate SEM.

 
A comparison of the effects of 2-CADO administered in non-dependent animals and during ethanol withdrawal is shown in Fig. 3Go. In non-dependent rats, 2-CADO produced full antinociceptive effects at the higher temperature setting (ED50 = 2.09 ± 0.29). During ethanol withdrawal, the 2-CADO dose–response curve was shifted 2-fold to the right (ED50 = 4.63 ± 0.65). The dose that produced a full effect in non-dependent animals (5.0 mg/kg) produced only 54% of the maximum peak effect in the rats exposed to chronic ethanol, and a dose of 10 mg/kg was necessary to obtain a full effect. In contrast, doses of 2-CADO administered in rats which received theophylline (1.0 mg/kg, twice daily) along with the ethanol diet produced effects no different from those in the non-dependent rats (ED50 = 2.35 ± 0.28). Baseline values averaged 6.8 ± 0.4 s and did not vary significantly between groups.



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Fig. 3. Comparison of the acute effects of cumulative doses of 2-chloroadenosine (2-CADO) during ethanol withdrawal. Four groups of six rats were used. Non-dependent, 2-CADO administered to rats not exposed to ethanol; EW, 2-CADO administered during ethanol withdrawal; + Theo, 2-CADO administered during ethanol withdrawal in the group which received theophylline (1.0 mg/kg, twice daily); MPE, mean peak effect. Brackets indicate SEM.

 

    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The purpose of this study was to examine the effects of subchronic administration of theophylline on ethanol-withdrawal-induced hyperalgesia. Because adenosine is known to mediate tolerance to ethanol (Nagy et al., 1991Go; Sapru et al., 1994Go; Wannamaker and Nagy, 1995Go; Coe et al., 1996Go), it is possible that adenosine receptors may mediate the ethanol-withdrawal-induced hyperalgesia.

During ethanol withdrawal, tail-flick latencies were significantly lower than in the group which received the dextrin control diet. Tail-flick latencies at the low intensity remained at the maximum (20 s) indicating that the decreased latencies at the high intensity were due to hyperalgesia rather than motor hyperexcitability during withdrawal. These findings are in agreement with earlier reports that withdrawal from chronic ethanol produces hyperalgesia (Gatch, 1999Go; Gatch and Lal, 1999Go). Subchronic administration of theophylline (0.5–1.0 mg/kg, twice daily) dose-dependently blocked the hyperalgesia seen during ethanol withdrawal and reduced withdrawal scores. These findings are in agreement with an earlier demonstration that subchronic administration of CPT blocked ethanol-withdrawal-induced anxiety (Gatch et al., 1999Go). It is important to note that, in both of these studies, the last dose of theophylline was given 24 h prior to testing, which suggests that the effects seen during withdrawal were not due to direct actions of theophylline.

Given that chronic administration of theophylline up-regulates adenosine A1 receptors in vitro (Szot et al., 1987Go), it is possible that the up-regulation of adenosine receptors by theophylline could overcome the desensitization to adenosine produced by chronic administration of ethanol. If so, this could account for our finding that subchronic administration of theophylline blocked ethanol-withdrawal-induced hyperalgesia. To date, no studies have directly demonstrated whether chronic theophylline prevents desensitization of adenosine transport by chronic ethanol. To provide behavioural evidence of this possibility, we tested the effects of an adenosine agonist during ethanol withdrawal. If this hypothesis is correct, an adenosine agonist should be less potent during ethanol withdrawal because of the desensitization to adenosine produced by chronic ethanol, and co-administration of theophylline with ethanol should prevent the decrease in potency.

In agreement with earlier studies, a non-selective adenosine agonist, 2-CADO, produced antinociception (Post, 1984Go; DeLander and Hopkins, 1986Go; Sawynok et al., 1986Go; Sosnowski et al., 1989Go). As predicted, 2-CADO was less potent during ethanol withdrawal than when administered to non-dependent rats. This finding is not surprising, in the light of in vitro evidence that 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., 1991Go; Sapru et al., 1994Go; Wannamaker and Nagy, 1995Go; Coe et al., 1996Go). In the present study, subchronic administration of theophylline (1.0 mg/kg, twice daily) prevented the loss of potency of 2-CADO during withdrawal, which agrees with the in vitro finding that chronic administration of theophylline up-regulates adenosine A1 receptors (Szot et al., 1987Go). It seems likely that chronic administration of theophylline can at least partially overcome the desensitization of adenosine receptors produced by ethanol, although other receptors may also be involved. Calcium channels also mediate ethanol tolerance (Pucilowski et al., 1989Go; Little et al., 1993Go), and the contribution of glutamate receptors to ethanol-induced antinociception has not been explored.

It should be noted that the theophylline + alcohol groups consumed significantly more ethanol than did the ethanol-alone group. It is not known whether the down-regulation of adenosine function by chronic ethanol intake plays any role in maintaining ethanol consumption, or whether the up-regulation of adenosine receptors by theophylline could possibly increase ethanol consumption. Regardless of the mechanism, it should be noted that increased ethanol consumption would be expected to increase the severity of withdrawal. However, the groups which received subchronic theophylline showed lower withdrawal scores and less hyperalgesia than the ethanol-alone group, despite the higher ethanol consumption.

In summary, subchronic administration of theophylline in rats exposed to chronic ethanol blocked the development of hyperalgesia during ethanol withdrawal. In addition, 2-CADO was less potent during ethanol withdrawal than in non-dependent rats, and this effect was blocked by subchronic theophylline. These findings add support for molecular studies which reported that adenosine receptors are involved in the development of tolerance to ethanol, and for behavioural studies showing that adenosine A1 agonists have been found to suppress ethanol withdrawal tremors and seizures in rats (Concas et al., 1994Go, 1996Go; Malec et al., 1996Go). Taken together, these findings suggest that adenosine receptors play an important role in ethanol tolerance and withdrawal, and that there may be an important role for adenosine agonists in the treatment of ethanol withdrawal. Direct evidence that chronic co-administration of theophylline with ethanol will prevent ethanol's desensitization of adenosine function is necessary to confirm the mechanism of our behavioural findings. However, the findings that adenosine agonists suppress seizures, withdrawal signs, and hyperalgesia during ethanol withdrawal suggest that these compounds may be of use as adjuncts for treatments of ethanol withdrawal.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
We thank Jorge Sanchez for expert technical assistance. This research was supported in part by NIH grants AA09567 and AA10545.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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