Interactions of the Anticonvulsants Diphenylhydantoin and Carbamazepine with Adenosine on Cerebral Cortical Neurons

Phillis, John W.

doi:10.1111/j.1528-1157.1984.tb03489.x

Cited by 53 publications

(20 citation statements)

References 44 publications

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“…), coadministrated with carbamazepine revealed that carbamazepine exerts its effect most probably through activation of adenosine A 1 receptors. This, taken together with previously reported data that carbamazepine binds to brain adenosine receptors (7,13) and has no effect on adenosine uptake (13,14), suggests direct interaction of carbamazepine with adenosine A 1 receptors, rather than an indirect action by enhancing adenosine tissue levels. Also, caffeine-and DPCPXinduced depressions are dose-and time-dependent and almost complete (up to 90%) at the higher doses of antagonists used, speaking in favor of the direct adenosine receptor-mediated action of carbamazepine.…”

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confidence: 89%

Peripheral Antinociception by Carbamazepine in an Inflammatory Mechanical Hyperalgesia Model in the Rat: a New Target for Carbamazepine?

Vučković¹,

Tomić²,

Stepanović-Petrović³

et al. 2006

J Pharmacol Sci

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Abstract. This study investigated whether carbamazepine could produce local peripheral antinociception in a rat model of inflammatory mechanical hyperalgesia, and whether adenosine receptors are involved. Carbamazepine (100 -1000 nmol / paw) coadministrated with a proinflammatory compound, concanavalin A, into the hind paw caused a significant dose-and time-dependent anti-hyperalgesia. Coadministration of caffeine (250 -1000 nmol / paw), a nonselective adenosine-receptor antagonist, as well as DPCPX (10 -30 nmol / paw), a selective adenosine A 1 -receptor antagonist, with carbamazepine, significantly depressed its antihyperalgesic effect. Drugs injected into the contralateral hind paw did not produce significant effects. These results suggest that carbamazepine produces local peripheral anti-hyperalgesia via peripheral adenosine A 1 receptors.Keywords: local carbamazepine, inflammatory mechanical hyperalgesia, adenosine A 1 receptor Carbamazepine is a well known anticonvulsant drug that has been widely used as an analgesic in the treatment of neuropathic pain. In recent years, increasing evidence appeared that carbamazepine is effective in different animal models of pain, but the sites and mechanisms of its action are not completely understood (1 -5).In our previous study, we have demonstrated that systemic carbamazepine reversed the hyperalgesia induced by intraplantar administration of a pro-inflammatory compound, concanavalin A (Con A), into the rat hind paw and that this effect is mediated via adenosine A 1 receptors (4). As it is well known that activation of both central and peripheral adenosine A 1 receptors inhibits pain in rodents (6), this finding raised further questions related to the potential involvement of the peripheral adenosine receptors in the carbamazepineinduced antinociception. The interaction of carbamazepine with central adenosine receptors has already been demonstrated in receptor binding studies (1, 7), as well as in a behavioral study of nociception (8). On the other hand, the interaction of carbamazepine with adenosine receptors in peripheral pain pathways has not been evaluated before.The present study had two objectives. First, to determine the effect of locally administered carbamazepine on inflammatory mechanical hyperalgesia in the hind paw of the rat. Second, to determine a potential involvement of adenosine receptors in the local peripheral action of carbamazepine by assessing the effect of caffeine (a nonselective adenosine A 1 and A 2 receptor antagonist) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (a selective adenosine A 1 -receptor antagonist) on carbamazepine-induced antinociception.Groups of 6 -8 male Wistar rats (180 -220 g) were used.

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confidence: 89%

Peripheral Antinociception by Carbamazepine in an Inflammatory Mechanical Hyperalgesia Model in the Rat: a New Target for Carbamazepine?

Vučković¹,

Tomić²,

Stepanović-Petrović³

et al. 2006

J Pharmacol Sci

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“…Diphenylhydantoin and valproate were ineffective (Weir et al, 1984). However, diphenylhydantoin and diazepam were shown to be potent inhibitors of adenosine uptake (Phillis, 1984;Phillis and Wu, 1982). A number of studies indicate that carbamazepine and phenobarbital are rather adenosine antagonists than agonists, carbamazepine at both adenosine receptor populations and phenobarbital at A1 adenosine receptors (Lohse etal., 1985;Skerrit etal., 1983;Weir etal., 1984).…”

Section: Discussionmentioning

confidence: 96%

Influence of CGS 15943 A (a nonxanthine adenosine antagonist) on the protection offered by a variety of antiepileptic drugs against maximal electroshock-induced seizures in mice

Czuczwar

Janusz

Szczepanik

et al. 1991

J. Neural Transmission

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CGS 15943 A (a nonxanthine adenosine antagonist) was studied on the protective efficacy of carbamazepine (60 min prior to the convulsive test), diazepam (60 min), diphenylhydantoin (120 min), phenobarbital (120 min), and valproate (30 min) against maximal electroshock-induced convulsions in mice. Moreover, the influence of the adenosine antagonist on 2-chloroadenosine (1 mg/kg, 20 min prior to the test)- and valproate (250 mg/kg, 30 min)-induced inhibitions of locomotor activity was also studied. CGS 15943 A (1 mg/kg) was given 15 min before both tests and all the drugs were administered i.p.. The adenosine antagonist (1 mg/kg) remained without influence upon the protective activity of all studied antiepileptics, reflected by their respective ED50 values against maximal electroshock. However, both 2-chloroadenosine and valproate-induced inhibitions of locomotor activity were attenuated by CGS 15943 A, which alone did not affect this parameter. However, CGS 15943 A (5 mg/kg) diminished the protection offered by diphenylhydantoin, increasing its ED50 value from 13 to 16 mg/kg. It may be concluded that the protection provided by common antiepileptic drugs against electroconvulsions seems independent of adenosine-mediated inhibition. In the case of diphenylhydantoin, one may suggest the involvement of purinergic transmission in the final anticonvulsant effect.

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“…Benzodiazepine derivatives, diazepam and clonazepam, as well as diphenylhydantoin, whose ICs0 concentrations were within the micromolar range, seemed the most active agents in this respect. Phenobarbital and carbamazepine exhibited considerably weaker potency as adenosine uptake inhibitors (Phillis, 1984;Phillis and Wu, 1982).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of agents enhancing purinergic transmission upon the antielectroshock efficacy of carbamazepine, diphenylhydantoin, diazepam, phenobarbital, and valproate in mice

Czuczwar

Szczepanik

Wamil

et al. 1990

J. Neural Transmission

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L-phenylisopropyladenosine (L-PIA; a preferential A1 adenosine agonist-0.05 mg/kg) offered no protection against electroconvulsions in mice but potentiated the anticonvulsant action of diazepam and valproate against maximal electroshock-induced seizures, decreasing the respective ED50 values from 9.5 to 4.0 mg/kg and from 250 to 185 mg/kg. However, it remained without effect on the protective activity of phenobarbital, carbamazepine and diphenylhydantoin. 5'-N-ethylcarboxamidoadenosine (NECA; a preferential A2 adenosine agonist-0.5 mg/kg) potentiated the efficacy of valproate. On the other hand, NECA (1 mg/kg) diminished the anticonvulsant action of phenobarbital (ED50 was elevated from 16.5 to 20.5 mg/kg), possessing no effect upon the protective action of carbamazepine. In addition, papaverine (20 mg/kg) significantly enhanced the protective efficacy of valproate and up to 40 mg/kg remained without influence upon the protective action of carbamazepine. However, papaverine (20 and 40 mg/kg) inhibited the anticonvulsive potential of phenobarbital. In the light of the results obtained A1 and A2 adenosine receptor-mediated events seem to possess different influences upon the protective effects of antiepileptic drugs.

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Interactions of the Anticonvulsants Diphenylhydantoin and Carbamazepine with Adenosine on Cerebral Cortical Neurons

Cited by 53 publications

References 44 publications

Peripheral Antinociception by Carbamazepine in an Inflammatory Mechanical Hyperalgesia Model in the Rat: a New Target for Carbamazepine?

Peripheral Antinociception by Carbamazepine in an Inflammatory Mechanical Hyperalgesia Model in the Rat: a New Target for Carbamazepine?

Influence of CGS 15943 A (a nonxanthine adenosine antagonist) on the protection offered by a variety of antiepileptic drugs against maximal electroshock-induced seizures in mice

Differential effects of agents enhancing purinergic transmission upon the antielectroshock efficacy of carbamazepine, diphenylhydantoin, diazepam, phenobarbital, and valproate in mice

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