Effects of nitrendipine, chlordiazepoxide, flumazenil and baclofen on the increased anxiety resulting from alcohol withdrawal.

1. Male hooded Lister rats were fed a liquid diet containing 10% absolute ethanol for 4-5 weeks. Control rats received the liquid diet in amounts controlled to produce equal weight gain. 2. The rats were tested 7.5 h after withdrawal of ethanol and 30 min after i.p. injection with nitrendipine, chlordiazepoxide or baclofen or 20 min after i.p. injection with flumazenil. 3. Nitrendipine (25-100 mg/kg) was unable to reverse the anxiogenic responses detected on withdrawal from ethanol, but the highest dose did reduce withdrawal tremor. 4. Chlordiazepoxide (10 mg/kg), flumazenil (4 mg/kg) and baclofen (1.25 mg/kg) significantly reversed the anxiogenic response detected on withdrawal from ethanol. 5. These reversals of ethanol withdrawal responses are similar to the reversal of the increased anxiety detected on withdrawal from chronic treatment with benzodiazepines. 6. The mechanisms and clinical implications of these drug-induced reversals are discussed.     

Consequences of amygdala kindling and repeated withdrawal from ethanol on amphetamine-induced behaviours

It has been shown previously that chronic ethanol treatment in mice leads to accelerated behavioural sensitization to psychomotor stimulants [Manley & Little (1997) J. Pharmacol. Exp. Ther., 281, 1330-1339], whilst repeated experience of ethanol withdrawal sensitizes pathways underlying seizure activity (Becker & Hale (1993) Alcohol Clin. Exp. Res., 17, 94-98]. The aim of the current experiment was to investigate the consequences of repeated withdrawal from ethanol on amphetamine-induced behaviours in the rat and compare this with animals with electrical kindling of the amygdala, a procedure that has been shown to enhance alcohol withdrawal seizures [Pinel et al. (1975) Can. J. Neurol. Sci., 2, 467-475]. For the kindling experiments, electrodes were surgically implanted in the left basolateral amygdala and were stimulated daily at the afterdischarge threshold until a criterion of three consecutive stage 5 seizures was reached. Fully kindled rats showed a marginally significant reduction in sensitivity to the locomotor stimulant effects of acute amphetamine compared with sham and partially kindled rats which had experienced subthreshold stimulation of the amygdala. Sham and partially kindled rats sensitized readily to the locomotor activating effects of amphetamine (0.125 mg/kg) following repeated treatments, but the fully kindled rats did not. Fully kindled rats also failed to show place preference conditioning to amphetamine (0.5 mg/kg). Rats, withdrawn three times from chronic ethanol (liquid-diet), kindled more quickly to PTZ (30 mg/kg, i.p.) than rats with the same overall exposure to ethanol (24 days) followed by a single withdrawal or control animals. However, there was no difference in the locomotor stimulating effects of acute amphetamine (0.25-1 mg/kg, i.p.), the rate of sensitization to amphetamine (0.125 mg/kg, i.p.) or amphetamine induced conditioned place preference (1 mg/kg, i.p.). These observations suggest that, in rats, repeated withdrawal from a relatively mild chronic ethanol treatment modulates neuronal systems that may also be involved in PTZ-induced kindling but not those involved in either the acute stimulant effects of amphetamine or behavioural sensitization or appetitive conditioning following repeated amphetamine administration. Behavioural changes following amygdala kindling differed from those following repeated ethanol withdrawal, suggesting that withdrawal kindling from a mild ethanol treatment differs in its effects from amygdala kindling.     

Reversal of morphine tolerance and dependence by melatonin: possible role of central and peripheral benzodiazepine receptors.

Possible reversal by melatonin of morphine-induced tolerance and dependence was studied in mice. A 10-day repeated injection regimen was followed to induce morphine tolerance and dependence. Co-administration of melatonin (1-10 mg/kg, i.p.) with morphine (10 mg/kg, s.c.) during the induction phase (day 1 to 9) reversed the development of opioid tolerance and dependence tested on 10th day. On the other hand acute administration of melatonin (1-10 mg/kg) on the 10th day, ie. during the expression phase of morphine dependence, it reduced the incidence of naloxone-induced withdrawal jumps without affecting the tolerance to analgesic effect. Co-administration of flumazenil (2 mg/kg, i.p.), a central benzodiazepine (BZ) receptor antagonist had no effect on melatonin response, whereas peripheral antagonist for BZ receptor PK11195 (2 mg/kg, i.p.) significantly reversed the attenuating effect of melatonin on physical dependence both during induction and expression phase of morphine tolerance and dependence. These observations suggest that melatonin reverses development of tolerance and dependence to morphine, and this action possibly involved peripheral benzodiazepine receptors.     

Adenosine receptor antagonists cancelled the ischemic tolerance phenomenon in gerbil

Pretreatment of the brain with sublethal ischemia has been reported to induce neuronal resistance to otherwise lethal ischemia, a phenomenon designated as ischemic tolerance. The protective mechanisms of the phenomenon are not known yet, however, recent experimental data suggest the involvement of adenosine receptor activation in the acquisition of tolerance. In this study, the effect of theophylline, a non-selective adenosine receptor antagonist, and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor antagonist, were investigated to ascertain if these drugs could cancel the protective effect of ischemic tolerance in the gerbil. DPCPX or theophylline was administered at 3 h after a short preconditioning ischemia, and 21 h later animals were subjected to lethal ischemia of 5 min duration. DPCPX at a dose of 1.0 mg/kg (i.p) and theophylline at a dose of 20 mg/kg (i.p) significantly reduced the protective effect of preconditioning in the CA1 hippocampal neurons. These findings suggest the involvement of adenosine receptor activation for the development of ischemic tolerance phenomenon.     

Pregnenolone sulfate,dehydroepiandrosterone sulfate and allotetrahydrodeoxycorticosterone affect rapid tolerance to the hypothermic effect of ethanol

Our previous study showed that the neurosteroids pregnenolone sulfate (PS) and epipregnanolone stimulated and blocked, respectively, the demonstration of chronic tolerance to the incoordinating effect of ethanol. The aim of the present study was to investigate the influence of three neurosteroids on the demonstration of tolerance to ethanol-induced hypothermia in mice using the rapid tolerance paradigm. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to ethanol-induced hypothermia. In the second, the influence of pretreatment of mice with PS (0.08 or 0.15 mg/kg, i.p.) or dehydroepiandrosterone sulfate (DHEAS; 0.15 or 0.20 mg/kg, i.p.) before ethanol (4.0 g/kg, i.p.) on rapid tolerance was studied. The third experiment examined the effect of allotetrahydrodeoxicorticosterone (ALLOT; 0.10 or 0.20 mg/kg, i.p.) before ethanol (4.0 g/kg, i.p.) on rapid tolerance. Results showed that pretreatment with PS or with DHEAS significantly facilitated the demonstration of rapid tolerance, whereas pretreatment with ALLOT interfered with the demonstration of tolerance to the hypothermic effect.     

L-NAME precipitates catatonia during ethanol withdrawal in rats

The effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a non-specific inhibitor of nitric oxide (NO) synthase, on catatonia in ethanol dependent rats was investigated. Ethanol was given to rats by a modified liquid diet. An isocaloric liquid diet without ethanol was also given to control rats. L-NAME (50, 100 and 200 mg/kg) and saline were injected intraperitoneally to ethanol-dependent rats 30 min before ethanol withdrawal. Then, catatonia was evaluated by vertical wire test at the 30th min, 2nd, 4th and 6th h of ethanol withdrawal. The injections were repeated 30 min before the observation of 6 h. Locomotor activity was also recorded for 5 min in the same observation intervals. L-NAME (200 mg/kg) or saline were also injected to ethanol non-dependent control rats. L-NAME (50 and 100 mg/kg) inhibited both incidence and intensity of the audiogenic seizures which appeared at 6 h of ethanol withdrawal. L-NAME (200 mg/kg) produced a significant augmentation in both incidence and intensity of the catatonia in ethanol dependent rats. This dose of L-NAME also reduced the locomotor activity of both ethanol dependent and non-dependent rats. The locomotor inhibitory effect was more prominent in ethanol-dependent group. The catatonia precipitating effect of L-NAME was not prevented by L-arginine (1 g/kg, i.p.), a NO precursor, pretreatment. In the naive rats, L-NAME also did not produce catatonia. These results indicate that L-NAME has a catatonia precipitating effect during ethanol withdrawal in rats and this effect seems to be independent from NO mediated mechanisms.     

Litter has an effect on the behavioural changes caused by the administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine and ethanol in mice

The aim of the work was to study the effects of litter and the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG) on the behaviour of mice after acute and chronic ethanol administration and withdrawal. Male outbred NIH/S mice, from 21 litters, were distributed among experimental groups and subjected to acute and chronic ethanol administration. After acute or chronic ethanol administration, the effects of L-NOARG on the behaviour of mice in the plus-maze test were studied. Acute ethanol (1 g/kg, i.p.), L-NOARG (20 and 40 mg/kg, i.p.) and their combination induced an anxiolytic effect. Furthermore, the values for the representatives of different litters tended to be either above or below the group mean, irrespective of the drug treatment. Chronic ethanol administration (23 days by inhalation) induced an anxiolytic effect and ethanol withdrawal induced an anxiogenic effect in the plus-maze. The administration of L-NOARG (20 mg/kg, i.p.) induced an anxiolytic effect in control mice and had no effect on ethanol-intoxicated mice, but attenuated the anxiogenic effect of ethanol withdrawal in the plus-maze. However, after chronic ethanol administration and withdrawal, litter had no effect on the behaviour of mice. If the litter is a significant determinant in the behaviour of outbred mice, then the use of information about the litter origin of animals could serve for the purposes of reduction. But only if this information is available from breeders.     

Differing acute interactions of ethanol with two structurally related dihydropyridines, nitrendipine and felodipine

Previous work showed that while several dihydropyridine calcium channel antagonists have protective effects against the ethanol withdrawal syndrome, felodipine differed in lacking this action. Dihydropyridine calcium channel antagonists have also been shown to potentiate the acute behavioral actions of ethanol. The present study compares the effects of felodipine on the acute effects of ethanol, with those of nitrendipine, a dihydropyridine previously shown to be effective against the ethanol withdrawal syndrome. Comparison was made at doses of the compounds that have previously been shown to produce similar displacement of dihydropyridine binding in central nervous system (CNS) tissue. Felodipine had a small potentiating effect on the general anesthetic effects of ethanol, but was considerably less effective in this respect than nitrendipine. Some potentiation of the ataxic effect of ethanol was seen after concurrent administration of felodipine, but this was less than that seen after nitrendipine. In the locomotor studies, both felodipine and nitrendipine significantly decreased the locomotor stimulation produced by ethanol; the effects of the two compounds were similar, but dose-dependency was not seen at the doses tested. Chronic administration of felodipine for 2 weeks did not produce tolerance to the sedative effect of felodipine or cross-tolerance to nitrendipine. After chronic administration of the felodipine, administration of an acute dose of ethanol resulted in an increase in locomotor activity, but this was not seen after chronic administration of nitrendipine or vehicle. The results, therefore, suggest that felodipine was considerably less effective in potentiating the acute effects of ethanol than nitrendipine at doses that were equi-effective in displacing central dihydropyridine binding. The interactions of these two calcium channel antagonists with ethanol, therefore, did not parallel their effects on central dihydropyridine binding.     

Chronic benzodiazepine administration facilitates the subsequent development of ethanol dependence

This study investigated the effect of chronic benzodiazepine (BZD) administration and its abrupt discontinuation on later subsequent ethanol consumption employing a free choice paradigm between water and increasing ethanol concentrations. In addition, we also studied the anxiolytic and reinforcing properties of ethanol assessed in the elevated plus maze (EPM) and in the conditioned place preference paradigm, respectively. Adult male Wistar rats were subjected to a chronic diazepam (DZM) treatment (2 mg/kg/day, i.p.) during 21 days. Twenty-four hours after that treatment and, in another experiment, 10 days after the last DZM injection, rats were subjected to an oral ethanol self-administration procedure (ethanol was increased in concentration (v/v) on 4 consecutive days as follows: 2%, 4%, 6%, 8% followed by an additional period of 8 days in which animals were offered a 10% (v/v) ethanol solution. Diazepam treated rats showed a higher ethanol intake and spontaneous signs of ethanol withdrawal when the access to ethanol was discontinued. These results were observed when ethanol was available at day 1 of withdrawal but not when DZM treated rats were initiated in the ethanol choice test 10 days after BDZ withdrawal. Furthermore, DZM treated rats exhibited an increased anxiolytic ethanol induced effect (1 g/kg, i.p.) in the EPM and a significant ethanol-induced conditioned place preference (1 g/kg, i.p.). These data suggest that early DZM treatment facilitates ethanol consumption and the development of ethanol dependence.     

Central corticotropin-releasing factor and benzodiazepine receptor systems are involved in the social isolation stress-induced decrease in ethanol sleep in mice

Social isolation stress has been demonstrated to decrease the hypnotic activity of ethanol in rodents. In this study, the role of central corticotropin-releasing factor (CRF) and GABA_A/benzodiazepine (BZD) receptor systems in the social isolation stress-induced decrease in the hypnotic activity of ethanol in mice was investigated by examining the effect of α-helical CRF_9–41 (αhCRF) and flumazenil, antagonists of CRF and BZD receptors, respectively, on ethanol-induced sleep in group-housed and socially isolated mice. We also tested whether social isolation stress affects the ability of ethanol to enhance the GABA-induced ³⁶Cl⁻ influx into a synaptoneurosomal preparation of mouse forebrain. Social isolation stress significantly decreased both the ethanol (4 g/kg i.p.)-induced and pentobarbital (50 mg/kg i.p.)-induced sleeping times, while this stress had no effect on chloral hydrate (325 mg/kg i.p.)-induced sleep. The i.c.v. injection of αhCRF (6.5 nmol) and flumazenil (33 nmol) antagonized the social isolation stress-induced decrease in the ethanol sleep without affecting ethanol sleep in group-housed animals. Social isolation stress significantly attenuated the ability of GABA to stimulate ³⁶Cl⁻ influx but this stress had no effect on the ability of ethanol to enhance GABA-induced ³⁶Cl⁻ influx. These results suggest that the functional changes in central CRF and GABA_A/BZD receptor systems are involved in the social isolation stress-induced decrease in the hypnotic activity of ethanol in mice. © 1997 Elsevier Science B.V. All rights reserved.     

Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice

Chemotherapy drugs treatment causes neuropathic pain, hyperalgesia and allodynia are common components of neuropathic pain, so effectively therapeutic strategy is required. In this study, we evaluated the antinociceptive effects of matrine on vincristine-induced neuropathic pain in mice. Vincristine (100 μg/kg i.p.) was administered once per day for 7 days (day 0–6) in mice. Matrine (15, 30, 60 mg/kg, i.p.) was repeated administration in early phase (day 0–6) or late phase (day 7–13). Hyperalgesia and allodynia were evaluated by withdrawal response using von Frey filaments, plantar and cold-plate on 7, 14 and 21 day. Injection of vincristine produced mechanical hyperalgesia and cold allodynia. Matrine was found to produce a protective role in both von Frey filaments and cold-plate test. The analysis of the effect supports the hypothesis that matrine is useful in therapy of vincristine-induced neuropathic pain. In conclusion, this study demonstrates that administration of matrine is associated with antinociceptive effect on mechanical and cold stimuli in a mice model of vincristine-induced neuropathy pain.     

Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice

We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.     

Quercetin, a bioflavonoid, attenuates thermal hyperalgesia in a mouse model of diabetic neuropathic pain

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, has been recognised as one of the most difficult types of pain to treat. Lack of understanding of etiology involved, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve pain. The aim of the present study was to explore the antinociceptive effect of a bioflavonoid, quercetin, both in control and streptozotocin (STZ)-induced diabetic mice. After 4 weeks of a single intraperitoneal injection of STZ (200 mg/kg), both control and diabetic mice were subjected to test thermal hyperalgesia by tail-immersion assay (warm water). Diabetic mice exhibited a significant hyperalgesia as compared with control mice. Quercetin (100 but not 50 mg/kg p.o.) produced a marked increase in tail-flick latencies in both diabetic and nondiabetic mice. Quercetin-induced increase in nociceptive threshold was reversed by naloxone (2 mg/kg i.p.), an opioid receptor antagonist. These preliminary results indicate an antinociceptive activity of quercetin, probably through modulation of opioidergic mechanism and point towards its potential to attenuate diabetic neuropathic pain.     

Rapid increase in basal acetylcholine release in the hippocampus of freely moving rats induced by withdrawal from long-term ethanol intoxication

The effect of ethanol withdrawal on hippocampal acetylcholine (ACh) release was investigated by brain microdialysis in rats rendered ethanol dependent by repeated forced administration of a 20% ethanol solution for 7 days. The behavioral signs of ethanol withdrawal were accompanied by an increase in hippocampal ACh output that was significantly 6 h after the last ethanol administration, reached a maximum (fourfold) at 12 h, and persisted for >72 h. Administration of diazepam (5 mg/kg, i.p.) or γ-hydroxybutyrate (1 g/kg, intragastric) 12 h after the last ethanol administration completely antagonized, within 30 min, the increase in ACh output induced by ethanol withdrawal. Thus, the rapid and marked increase in ACh output might contribute to the changes in cognitive function associated with ethanol withdrawal, and the septohippocampal cholinergic system may play a major role in the response to withdrawal of addictive drugs.     

Evidence for opiate-activated NMDA processes masking opiate analgesia in rats

The acute interaction between opioid receptors and N-methyl-D-aspartate (NMDA) receptors on nociception was examined in rats using tail-flick and paw-pressure vocalisation tests. When injected at various times (1 to 6 h) after morphine (5 to 20 mg/kg, i.v.) or fentanyl (4x40 microgram/kg, i.v.), the opioid receptor antagonist naloxone (1 mg/kg, s.c.) not only abolished the opiate-induced increase in nociceptive threshold, but also reduced it below the basal value (hyperalgesia). The noncompetitive NMDA receptor antagonist MK-801 (0.15 or 0.30 mg/kg, s.c.) prevented the naloxone-precipitated hyperalgesia and enhanced the antinociceptive effects of morphine (7.5 mg/kg, i.v.) and fentanyl (4x40 microgram/kg, i.v.). These results indicate that the antinociceptive effects of morphine and fentanyl, two opiate analgesics widely used in humans in the management of pain, are blunted by concomitant NMDA-dependent opposing effects which are only revealed when the predominant antinociceptive effect is sharply blocked by naloxone. This study provides new rationale for beneficial adjunction of NMDA receptor antagonists with opiates for relieving pain by preventing pain facilitatory processes triggered by opiate treatment per se.     

Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor increases pentylenetetrazol seizure threshold in mice: possible involvement of adenosinergic mechanism

Multiple lines of investigations have explored the role of cyclooxygenases (COX) in epilepsy and related neuropsychiatric disorders. Cyclooxygenase particularly, COX-2 expression was found to increase in brain during seizure paradigms. The present study was carried out to investigate the effect of rofecoxib, a selective COX-2 inhibitor against pentylenetetrazol (PTZ i.v.) seizure threshold in mice. The study was further extended to elucidate the possible involvement of adenosinergic mechanism in mediating its anticonvulsant action. Minimal dose of PTZ (i.v., mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of PTZ convulsions were noted as an index of seizure threshold. Acute administration of rofecoxib (4mg/kg, i.p.) before PTZ infusion produced an elevation of seizure threshold for all the phases of convulsions. A lower dose of rofecoxib (2mg/kg, i.p.) showed an increase in PTZ seizure threshold for the onset of myoclonic jerks and tonic extension phases but not for generalized clonus. A still lower dose of rofecoxib (1mg/kg, i.p.) failed to increase the threshold in any of the convulsive phases induced by PTZ i.v. infusion. Pretreatment with sub-effective dose of rofecoxib (1mg/kg, i.p.) enhanced the action of sub-protective doses of either adenosine (25mg/kg, i.p.) or 2-chloroadenosine (1 or 2mg/kg, i.p.) in increasing the seizure threshold. On the contrary, treatment with caffeine (100 or 200mg/kg, i.p.) or theophylline (50 or 100mg/kg, i.p.), both non-selective A(1)/A(2) adenosine receptor antagonists reversed the anticonvulsant effect of rofecoxib (4mg/kg, i.p.). Further, dipyridamole (5mg/kg, i.p.), an adenosine uptake inhibitor displayed an anticonvulsant effect with rofecoxib (1mg/kg, i.p.). The study for the first time demonstrated the possible involvement of adenosinergic system in the anticonvulsant effects of rofecoxib against PTZ i.v. seizure threshold paradigm in mice.     

SYM 2081, an agonist that desensitizes kainate receptors,attenuates capsaicin and inflammatory hyperalgesia

Excitatory amino acids acting at non-NMDA receptors contribute to transmission of nociceptive information. SYM 2081 ((2S,4R)-4-methyl glutamic acid) desensitizes kainate receptors, one subtype of non-NMDA receptors, to subsequent release of excitatory amino acids and thus may attenuate transmission of nociceptive information. To determine if SYM 2081 can prevent development of hyperalgesia, SYM 2081 (10, 50 or 100 mg/kg, i.p.) was administered prior to injection of capsaicin into the hindpaw of rats, which produces mechanical and heat hyperalgesia. To determine if SYM 2081 can reduce ongoing inflammatory hyperalgesia, SYM 2081 (10 or 100 mg/kg, i.p.) was administered after development of carrageenan-evoked hyperalgesia. Intraplantar injection of capsaicin produced an increase in hindpaw withdrawal frequency to mechanical stimuli (from 4+/-2 to 41+/-7%; mean+/-S.E.M.) and a decrease in withdrawal latency to heat (from 12.3+/-0.3 to 5.9+/-0.4 s) in rats that received vehicle. In contrast, rats that received SYM 2081 (100 mg/kg) prior to injection of capsaicin exhibited a lower hindpaw withdrawal frequency (18+/-4%) and a longer withdrawal latency (7.7+/-0.5 s). Intrathecal (1-100 microg/5 microl), but not intraplantar (10 or 100 microg/50 microl), injection of SYM 2081 attenuated the development of capsaicin-evoked heat hyperalgesia suggesting that SYM 2081's antihyperalgesic effects were due to its central effects. Furthermore, SYM 2081 completely reversed ongoing carrageenan-evoked mechanical hyperalgesia and partially (approximately 50%) reversed ongoing heat hyperalgesia. The present study demonstrates that administration of a high-potency ligand that selectively desensitizes kainate receptors attenuates the development of mechanical and heat hyperalgesia and attenuates ongoing inflammatory hyperalgesia.     

Dopamine release is involved in antinociceptive effect of theophylline

The methylxanthines, e.g., theophylline, are widely used for the treatment of bronchial asthma. Additionally, a pain relieving effect of theophylline has been reported in patients as well as in experimental animals. The mechanism of this antinociceptive action is not clear. In this study, involvement of dopaminergic system in theophylline-induced antinociception was evaluated using tail flick test model. Swiss albino mice, (either sex, weighing 25-30 g) with base line tail flick latencies (TFL) between 2.0 and 3.5 s, were used. TFL was recorded before and at intervals of 15, 30, 45, and 60 min. after drug treatment. The experimental protocol was duly approved by the Institutional Animal Ethics Committee, All India Institute of Medical Sciences, New Delhi, India. To determine the role of dopaminergic system, the mice were pretreated with either D1 or D2 dopaminergic receptor antagonists SCH 23390 and haloperidol, respectively, prior to treatment with theophylline. Another group of animals received apomorphine along with theophylline. The dose of theophylline used, i.e., 10 mg/kg, intraperitoneally (i.p.), had shown a significant increase in TFLs. The theophylline-induced antinociception, 10 mg/kg, i.p., was reversed by pretreatment with both D1 and D2 dopaminergic receptor antagonists SCH 23390 and haloperidol as well as with apomorphine (1 mg/kg) pretreatment. The results suggest that theophylline-induced antinociception is due to release of dopamine.     

Chronic treatment with ethanol produces supersensitivity to oxotremorine

1. The effect of chronic treatment with ethanol (14% v:v in drinking water) on the physiological endpoint core temperature which is partially regulated by a muscarinic mechanism was measured in adult male rats (n = 8). 2. One and two weeks of treatment were associated with enhancement of the hypothermic response to oxotremorine, 0.25 mg/kg ip (p = 0.0005 and p = 0.0001, respectively). 3. The sample remained supersensitive to this muscarinic agonist 48 and 96 hours after the discontinuation of treatment (p = 0.0014 and p = 0.013 respectively). 4. Repeated injections of oxotremorine, 0.25 mg/kg ip, every other day for 10 days did not produce carry-over effects in a control experiment. 5. The results suggest that ethanol renders muscarinic mechanisms supersensitive during chronic treatment and that supersensitivity remains up to 96 hours following withdrawal.     

The role of ethanol in diluents of drugs that protect mice from hypoxia

This study evaluates the hypothesis that ethanol alone, or in diluents for drugs used to protect hypoxic mice, is responsible in part for an increased tolerance to hypoxia (4-5% oxygen). The change in hypoxic tolerance following i.v. or i.p. administration of ethanol, diazepam, nimodipine and various diluent components was measured. Diazepam (50 mg/kg i.v.) increased hypoxic tolerance to 700 +/- 47% (n = 11) of saline control, its diluent increased hypoxic tolerance to 468 +/- 60% (n = 10) of saline control but the ethanol component of the diluent accounted for almost half of this diluent effect. Nimodipine (2 mg/kg i.p.), a calcium antagonist, increased tolerance to 180 +/- 18% of control (n = 19) and nimodipine diluent showed an even greater increase to 226 +/- 25% of control (n = 15). In this case essentially all of the protective effect of nimodipine diluent (81.3%) is accounted for by ethanol. Dose response curves indicate the maximum ethanol induced increase in hypoxic tolerance was approximately 335% of control at a dose of 2.4 g/kg. Buffers, etc. in the diluents evidently add to the protective effect of ethanol. Our data clearly indicate ethanol is the important component of some treatments which protect mice from hypoxia. The pharmacological activity of ethanol, even when used in a diluent, should not be ignored in evaluating therapeutic intervention for protection from hypoxia.