Maja A. Tomić

The Antinociceptive Effects of Anticonvulsants in a Mouse Visceral Pain Model

BACKGROUND:There is evidence supporting the antinociceptive effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in various models of neuropathic pain as well as inflammatory somatic pain. Data are lacking on the antinociceptive potential of these drugs against visceral pain. In this study, we examined and compared the effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in the writhing test as a visceral pain model in the mouse. In addition, the influence of these anticonvulsants on motor performance was examined to compare the tolerability of these anticonvulsants when used against acute visceral pain. METHODS:The antinociceptive effects of these anticonvulsants were examined in the acetic acid writhing test in mice. The side effect propensity of these drugs was examined using the rotarod test. RESULTS:Carbamazepine (25–60 mg/kg; p.o.), oxcarbazepine (10–40 mg/kg; p.o.), gabapentin (10–70 mg/kg; p.o.), and topiramate (5–30 mg/kg; p.o.) caused a significant dose-dependent reduction the number of writhes in the writhing test. In the rotarod test, carbamazepine (60–140 mg/kg; p.o.) and oxcarbazepine (120–450 mg/kg; p.o.) significantly reduced the time spent on the rotarod in a dose- and time-dependent manner. Gabapentin (1000–2000 mg/kg; p.o.) and topiramate (400–1500 mg/kg; p.o.) did not produce significant impairment of motor performance at the highest doses used. The therapeutic index (motor impairing dose TD50/writhing ED50) values were topiramate (>148.5) > gabapentin (>60.2) > oxcarbazepine (15.2) > carbamazepine (2.3). CONCLUSIONS:These results indicate that oxcarbazepine, gabapentin, and topiramate are effective in the writhing model in mice, in a dose range, which is not related to motor impairment; topiramate is the most potent and the most tolerable drug.

The anti-hyperalgesic effects of carbamazepine and oxcarbazepine are attenuated by treatment with adenosine receptor antagonists.

Abstract The antinociceptive effects of carbamazepine and oxcarbazepine, and the influence of caffeine, were examined in a paw pressure test in rats. Carbamazepine (10–40 mg/kg; intraperitoneal, i.p.) and oxcarbazepine (40–160 mg/kg; i.p.) caused a significant dose‐dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A), intraplantarly (i.p1.). A comparable pattern of antinociceptive effect of carbamazepine and oxcarbazepine was observed; the only difference is their potency, in that carbamazepine was about three times more potent than oxcarbazepine. Caffeine (5–20 mg/kg; i.p.), a non‐selective adenosine receptor antagonist, significantly depressed the antinociceptive effects of carbamazepine and oxcarbazepine, in a dose‐ and time‐dependent manner. Also, a significant depression of the antinociceptive effects of carbamazepine and oxcarbazepine was observed by pretreatment with 1,3‐dipropyl‐8‐cyclopentylxantine (DPCPX, 0.4 and 0.8 mg/kg; i.p.), an adenosine A1 receptor antagonist. These findings indicate that, in a paw inflammatory hyperalgesia in rats, the antinociceptive effects of both drugs are, at least partially, mediated by adenosine A1 receptors. In conclusion, the present study suggests the potential clinical importance of carbamazepine and oxcarbazepine in the treatment of inflammatory pain. In addition, caffeine consumption could possibly depress the analgesic effects of both anticonvulsive drugs.

The effects of α2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain

&NA; In this study, the effects of yohimbine (&agr;2‐adrenoceptor antagonist) and clonidine (&agr;2‐adrenoceptor agonist) on anti‐hyperalgesia induced by carbamazepine and oxcarbazepine in a rat model of inflammatory pain were investigated. Carbamazepine (10–40 mg/kg; i.p.) and oxcarbazepine (40–160 mg/kg; i.p.) caused a significant dose‐dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A, intraplantarly) in a paw pressure test in rats. Yohimbine (1–3 mg/kg; i.p.) significantly depressed the anti‐hyperalgesic effects of carbamazepine and oxcarbazepine, in a dose‐ and time‐dependent manner. Both drug mixtures (carbamazepine–clonidine and oxcarbazepine–clonidine) administered in fixed‐dose fractions of the ED50 (1/2, 1/4 and 1/8) caused significant and dose‐dependent reduction of the hyperalgesia induced by Con A. Isobolographic analysis revealed a significant synergistic (supra‐additive) anti‐hyperalgesic effect of both combinations tested. These results indicate that anti‐hyperalgesic effects of carbamazepine and oxcarbazepine are, at least partially, mediated by activation of adrenergic &agr;2‐receptors. In addition, synergistic interaction for anti‐hyperalgesia between carbamazepine and clonidine, as well as oxcarbazepine and clonidine in a model of inflammatory hyperalgesia, was demonstrated.

The antihyperalgesic effect of levetiracetam in an inflammatory model of pain in rats: mechanism of action.

BACKGROUND AND PURPOSE Levetiracetam, a novel antiepileptic drug, has recently been shown to have antinociceptive effects in various animal models of pain. The purpose of this study was to investigate the antihyperalgesic effect of levetiracetam and its mechanism of action, by examining the involvement of GABAergic, opioidergic, 5‐hydroxytryptaminergic (5‐HTergic) and adrenergic systems in its effect, in a rat model of inflammatory pain.

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

BACKGROUND: We have recently shown that levetiracetam, administered systemically, exerts an antihyperalgesic effect in a rat inflammatory pain model. In this study, we examined whether levetiracetam has local peripheral antihyperalgesic/anti-edematous effects in the same model of localized inflammation and whether opioidergic, adrenergic, purinergic, 5-HTergic, and GABAergic receptors are involved in its antihyperalgesic action. METHODS: Rats were intraplantarly (IPL) injected with carrageenan. A paw pressure test was used to determine the effect/s of (a) levetiracetam when applied IPL, on carrageenan-induced hyperalgesia, and (b) naloxone (a nonselective opioid receptor antagonist), CTAP (a selective &mgr;-opioid receptor antagonist); yohimbine (a selective &agr;2-adrenoceptor antagonist), BRL 44408 (a selective &agr;2A-adrenoceptor antagonist), MK-912 (a selective &agr;2C-adrenoceptor antagonist); caffeine (a nonselective adenosine receptor antagonist), DPCPX (a selective adenosine A1 receptor antagonist); methysergide (a nonselective 5-HT receptor antagonist), GR 127935 (a selective 5-HT1B/1D receptor antagonist); and bicuculline (a selective GABAA receptor antagonist), all applied IPL, on the levetiracetam-induced antihyperalgesia. Moreover, levetiracetam’s influence on paw inflammatory edema was measured by plethysmometry. RESULTS: Levetiracetam (200–1000 nmol/paw) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia and edema induced by carrageenan. Naloxone (75–300 nmol/paw), CTAP (1–5 nmol/paw); yohimbine (130–520 nmol/paw), BRL 44408 (50–200 nmol/paw), MK-912 (5–20 nmol/paw); caffeine (500–1500 nmol/paw), DPCPX (3–30 nmol/paw); methysergide (10–100 nmol/paw) and GR 127935 (50–200 nmol/paw); but not bicuculline (400 nmol/paw), significantly depressed the antihyperalgesic effects of levetiracetam (1000 nmol/paw). The effects of levetiracetam and antagonists were attributed to local peripheral effects because they were not observed after administration into the contralateral hind-paw. CONCLUSIONS: Our results show that levetiracetam produces local peripheral antihyperalgesic and anti-edematous effects in a rat model of localized inflammation. Antihyperalgesia is at least in part mediated by peripheral &mgr;-opioid, &agr;2A,C-adrenergic, A1 adenosine, and 5-HT1B/1D receptors, but not by GABAA receptors. These findings could contribute toward a better understanding of the analgesic effects of levetiracetam, and improved treatments of inflammatory pain with a lower incidence of systemic side effects and drug interactions of levetiracetam.

Analysis of the antinociceptive interactions in two-drug combinations of gabapentin, oxcarbazepine and amitriptyline in streptozotocin-induced diabetic mice

Antiepileptic and antidepressant drugs are the primary treatments for pain relief in diabetic neuropathy. Combination therapy is a valid approach in pain treatment, where a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of two-drug combinations of gabapentin, oxcarbazepine, and amitriptyline on nociception in diabetic mice and aimed to determine the type of interaction between components. The nociceptive responses in normal and diabetic mice were assessed by the tail-flick test. The testing was performed before and three weeks after the diabetes induction with streptozotocin (150mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10-40mg/kg; p.o.) and oxcarbazepine (20-80mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5-60mg/kg; p.o.) produced weak antinociceptive effect. In normal mice, neither of the drugs produced antinociception. Gabapentin and oxcarbazepine, co-administered in fixed-dose fractions of the ED(50) to diabetic mice, induced significant, dose-dependent antinociception. Isobolographic analysis revealed synergistic interaction. Oxcarbazepine (10-60mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) and gabapentin (10-30mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) combinations significantly and dose-dependently reduced nociception in diabetic mice. Analysis of the log dose-response curves for oxcarbazepine or gabapentin in a presence of amitriptyline and oxcarbazepine or gabapentin applied alone, revealed a synergism in oxcarbazepine-amitriptyline and additivity in gabapentin-amitriptyline combination. These findings provide new information about the combination therapy of painful diabetic neuropathy and should be explored further in patients with diabetic neuropathy.

Antihyperalgesic/antinociceptive Effects of Ceftriaxone and Its Synergistic Interactions with Different Analgesics in Inflammatory Pain in Rodents

Background:The &bgr;-lactam antibiotic ceftriaxone stimulates glutamate transporter GLT-1 expression and is effective in neuropathic and visceral pain models. This study examined the effects of ceftriaxone and its interactions with different analgesics (ibuprofen, celecoxib, paracetamol, and levetiracetam) in somatic and visceral pain models in rodents. Methods:The effects of ceftriaxone (intraperitoneally/intraplantarly), analgesics (orally), and their combinations were examined in the carrageenan-induced paw inflammatory hyperalgesia model in rats (n = 6–12) and in the acetic acid-induced writhing test in mice (n = 6–10). The type of interaction between ceftriaxone and analgesics was determined by isobolographic analysis. Results:Pretreatment with intraperitoneally administered ceftriaxone (10–200 mg/kg per day) for 7 days produced a significant dose-dependent antihyperalgesia in the somatic inflammatory model. Acute administration of ceftriaxone, via either intraperitoneal (10–200 mg/kg) or intraplantar (0.05–0.2 mg per paw) routes, produced a significant and dose-dependent but less efficacious antihyperalgesia. In the visceral pain model, significant dose-dependent antinociception of ceftriaxone (25–200 mg/kg per day) was observed only after the 7-day pretreatment. Isobolographic analysis in the inflammatory hyperalgesia model revealed approximately 10-fold reduction of doses of both drugs in all examined combinations. In the visceral nociception model, more than 7- and 17-fold reduction of doses of both drugs was observed in combinations of ceftriaxone with ibuprofen/paracetamol and celecoxib/levetiracetam, respectively. Conclusions:Ceftriaxone exerts antihyperalgesia/antinociception in both somatic and visceral inflammatory pain. Its efficacy is higher after a 7-day pretreatment than after acute administration. The two-drug combinations of ceftriaxone and the nonsteroidal analgesics/levetiracetam have synergistic interactions in both pain models. These results suggest that ceftriaxone, particularly in combinations with ibuprofen, celecoxib, paracetamol, or levetiracetam, may provide useful approach to the clinical treatment of inflammation-related pain.

Antihyperalgesic and Antiedematous Activities of Bisabolol‐Oxides‐Rich Matricaria Oil in a Rat Model of Inflammation

From the dried flower heads of Matricaria recutita L., essential oil was isolated by hydrodistillation, and in the obtained blue oil, α‐bisabolol oxide A (21.5%), α‐bisabolol oxide B (25.5%) and (Z)‐spiroether (cis‐en‐yn‐spiroether) (10.3%) were identified as the main compounds, by gas chromatography (GC) and GC–mass spectrometry analyses. The antihyperalgesic effects of this oil were examined in a rat model of inflammation induced by carrageenan, through a modified ‘paw‐pressure’ test. Antiedematous effects were examined in a rat model of inflammation induced by carrageenan, dextran and histamine, through plethysmometry. Matricaria oil (25, 50 and 100 mg/kg, p.o.) exhibited a significant dose‐dependent reduction of hyperalgesia and edema induced by carrageenan in both prophylactic and therapeutic treatment schemes. It was more efficacious in the prophylactic treatment scheme, and the corresponding median effective dose (ED50) ± standard error of the mean (SEM) values were 49.8 ± 6.0 and 42.4 ± 0.2 mg/kg for antihyperalgesic and antiedematous effects, respectively. Prophylactic treatments with matricaria oil (25, 50 and 100 mg/kg, p.o.) caused a significant dose‐dependent antiedematous effect in dextran‐induced edema with lower efficacy than in the carrageenan model. In a dose of 100 mg/kg, p.o., matricaria oil caused a slight reduction of histamine‐induced edema. These results suggest that bisabolol‐oxide‐rich matricaria oil may be effective against pain and edema present in various inflammatory conditions, which supports matricaria traditional uses. Copyright

Synergistic interactions between paracetamol and oxcarbazepine in somatic and visceral pain models in rodents.

BACKGROUND:Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of coadministered paracetamol, a widely used non-opioid analgesic, and oxcarbazepine, a relatively novel anticonvulsant with analgesic properties, in a rat model of paw inflammatory hyperalgesia and in a mice model of visceral pain and determined the type of interaction between components. METHODS:The effects of paracetamol, oxcarbazepine, and their combinations were examined in carrageenan-induced (0.1 mL, 1%) paw inflammatory hyperalgesia in rats and in an acetic acid–induced (10 mg/kg, 0.75%) writhing test in mice. In both models, drugs were coadministered in fixed-dose fractions of the 50% effective dose (ED50), and type of interaction was determined by isobolographic analysis. RESULTS:Paracetamol (50–200 mg/kg peroral), oxcarbazepine (40–160 mg/kg peroral), and their combination (1/8, 1/4, 1/3, and 1/2 of a single drug ED50) produced a significant, dose-dependent antihyperalgesia in carrageenan-injected rats. In the writhing test in mice, paracetamol (60–180 mg/kg peroral), oxcarbazepine (20–80 mg/kg peroral), and their combination (1/16, 1/8, 1/4, and 1/2 of a single drug ED50) significantly and dose dependently reduced the number of writhes. In both models, isobolographic analysis revealed a significant synergistic interaction between paracetamol and oxcarbazepine, with a >4-fold reduction of doses of both drugs in combination, compared with single drugs ED50. CONCLUSIONS:The synergistic interaction between paracetamol and oxcarbazepine provides new information about combination pain treatment and should be explored further in patients, especially with somatic and/or visceral pain.

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

Background/Aims: The purpose of this study was to investigate the involvement of GABAergic mechanisms in the antihyperalgesic effect of carbamazepine and oxcarbazepine by examining the effect of bicuculline (GABAA receptor antagonist) on these effects of antiepileptic drugs. Methods: Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: (1) the development of hyperalgesia induced by Con A; (2) the effects of carbamazepine/oxcarbazepine on Con A-induced hyperalgesia, and (3) the effects of bicuculline on the carbamazepine/oxcarbazepine antihyperalgesia. Results: Intraperitoneally injected bicuculline (0.5–1 mg/kg, i.p.) exhibited significant suppression of the systemic antihyperalgesic effects of carbamazepine (27 mg/kg, i.p.) and oxcarbazepine (80 mg/kg, i.p.). When applied intraplantarly, bicuculline (0.14 mg/paw, i.pl.) did not produce any change in the peripheral antihyperalgesic effects of carbamazepine (0.14 mg/paw, i.pl.) and oxcarbazepine (0.5 mg/paw, i.pl.). Bicuculline alone did not produce an intrinsic effect in the paw-pressure test. Conclusion: These results indicate that the antihyperalgesic effects of carbamazepine and oxcarbazepine against inflammatory hyperalgesia involve in part the GABAergic inhibitory modulation of pain transmission at central, but not at peripheral sites, which is mediated via GABAA receptor activation.