Role of alpha2-adrenoceptors in the local peripheral antinociception by carbamazepine in a rat model of inflammatory mechanical hyperalgesia.
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 (i.pl.) 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 (i.pl.) 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.
Vuckovic
S
S
Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Doktora Subotića 1, Belgrade, Serbia. svuckovic@med.bg.ac.yu
Tomić
M
M
Stepanović-Petrovic
R
R
Ugresic
N
N
Prostran
M
M
Boskovic
B
B
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology* / Q000627:therapeutic use; D003208:Concanavalin A / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006614:Hindlimb; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D007267:Injections; D008297:Male; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013997:Time Factors; D015016:Yohimbine / Q000494:pharmacology / Q000627:therapeutic use
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D018712:Analgesics, Non-Narcotic; D018341:Receptors, Adrenergic, alpha-2; D003208:Concanavalin A; D015016:Yohimbine; D002220:Carbamazepine