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      Role of alpha2-adrenoceptors in the local peripheral antinociception by carbamazepine in a rat model of inflammatory mechanical hyperalgesia.

      Methods and findings in experimental and clinical pharmacology

      therapeutic use, Adrenergic alpha-2 Receptor Antagonists, pharmacology, Yohimbine, Time Factors, physiology, Receptors, Adrenergic, alpha-2, Rats, Wistar, Rats, methods, Pain Measurement, prevention & control, physiopathology, Pain, Male, Injections, chemically induced, Inflammation, Hyperalgesia, Hindlimb, Drug Therapy, Combination, Drug Synergism, Dose-Response Relationship, Drug, Disease Models, Animal, toxicity, administration & dosage, Concanavalin A, Carbamazepine, Animals, Analgesics, Non-Narcotic, Adrenergic alpha-Antagonists

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          The anticonvulsant carbamazepine was recently shown to possess local peripheral antinociceptive properties. In this study, we investigated whether alpha2-adrenergic receptors are involved in the local peripheral antihyperalgesic effects of carbamazepine and determined the type of interaction between carbamazepine and clonidine, an alpha2-adrenoceptor agonist. Intraplantar ( coadministration of either carbamazepine (100-1000 nmol/paw) or clonidine (1.9-3.7 nmol/paw) with the proinflammatory compound concanavalin A (Con A; 0.8 mg/paw) caused a significant dose- and time-dependent reduction of the difference between the forces exerted by a rat's hind paws in a modified paw-pressure test. The coadministration of 260 and 520 nmol/paw ( yohimbine, an alpha2-adrenoceptor antagonist, with carbamazepine, significantly depressed the local antihyperalgesic effect in a dose- and time-dependent manner whereas yohimbine by itself did not have any effect. The administration of a mixture of carbamazepine and clonidine at fixed dose fractions (1/4, 1/2 and 3/4) of ED50 caused a significant and dose-dependent reduction of Con A-induced hyperalgesia. Isobolographic analysis revealed an additive interaction. These results suggest that alpha2-adrenoceptors play a role in the local peripheral antihyperalgesic effects of carbamazepine and that local peripheral coadministration of carbamazepine with clonidine results in an additive antihyperalgesic effect.

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