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

Abstract

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.

The Local Peripheral Antihyperalgesic Effect of Levetiracetam and Its Mechanism of Action in an Inflammatory Pain Model

“…Other antiepileptics such as phenytoin, gabapentin, ethosuximide, carbamazepine, oxcarbazepine, and topiramate also produced local peripheral antinociceptive/antihyperalgesic effects in thermal and inflammatory animal pain models. [16][17][18][19] In all these studies, local peripheral doses of the antiepileptics were many times lower than the lowest effective systemic dose. Likewise, in the present study, significant local effects of levetiracetam (200-1000 nmol/paw = 0.034-0.17 mg/rat, corresponds to 0.17-0.85 mg/kg) were attainable with much lower doses (up to 59 times lower) than the lowest effective systemic dose that was determined in our previous study (10 mg/kg).…”

“…We showed that the antiepileptics carbamazepine and oxcarbazepine produced their peripheral antinociceptive effects through A 1 receptors. 17,18 Because there are no data showing that levetiracetam binds to adenosine A 1 receptors, we speculate that the local peripheral antihyperalgesic effect of levetiracetam is most likely mediated through indirect activation of peripheral adenosine A 1 receptors. Taken together, it is possible that peripheral antinociception induced by levetiracetam requires the physical presence of multiple μ-opioid, α 2 -adrenergic, and A 1 adenosine receptors on the primary afferents, according the finding of Aley and Levine 32 who found that despite the antinociception that is produced by the activation of μ, α 2 , or A 1 receptors, it is possible that these receptors may not act independently, but rather require to be associated with a complex to produce antinociception.…”

Anti-hyperalgesic effect of systemic magnesium sulfate in carrageenan-induced inflammatory pain in rats: influence of the nitric oxide pathway

“…The intensity of hyperalgesia was quantified as the differences in pressures [d (g)] applied before and after injection of carrageenan (control d), or before and after injection of carrageenan plus drugs (test d). Analgesic activity (AA %) for each rat was calculated according to the formula [20]:…”

GABAergic Mechanisms Are Involved in the Antihyperalgesic Effects of Carbamazepine and Oxcarbazepine in a Rat Model of Inflammatory Hyperalgesia

“…Next, we retested the peripheral antihyperalgesic activity of the equi-effective doses of carbamazepine and oxcarbazepine previously determined [7,8] ( fig. 1, C).…”

“…There is increasing evidence that both antiepileptics are effective in different animal models of pain [2][3][4][5][6] . We have shown, in a paw inflammatory hyperalgesia model in rats, that carbamazepine and oxcarbazepine produce antihyperalgesic effects which are mediated by activation of central and peripheral adenosine (A 1 ) and adrenergic ( ␣ 2 ) receptors [4,5,[7][8][9] , but the role of ␥ -aminobutyric acid (GABA) receptors in this action has not been established precisely.…”