Sonja Vučković

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 synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl

The synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been effected in 5 steps, starting from N-ethoxycarbonyl-4-piperidone (approximately 20% overall yield). In the key step, N-phenylation of secondary aliphatic amide intermediare was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary pharmacological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl.

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.

Fentanyl Analogs: Structure-Activity-Relationship Study

Fentanyl is the prototype of the 4-anilidopiperidine class of synthetic opioid analgesics. This study was aimed to review the structure-activity-relationship (SAR) of fentanyl analogs substituted in the position 3, or 4 of the piperidine ring. Pharmacological results show that the groups in position 3 of the piperidine ring, which are larger than methyl, severely reduce the analgesic potency compared to fentanyl. It is likely that the steric factor alone (i.e. voluminosity of the group and cis/trans isomerism), rather than the polarity and/or chemical reactivity, plays a crucial role in the analgesic potency of this series. Although the duration of action, in general, does not depend on the stereochemistry, longer action of the most potent 3-alkyl fentanyl analogs such as cis-3-methyl- and cis-3-ethyl fentanyl, is more likely influenced by pharmacodynamic, rather than pharmacokinetic variables. Also, it is possible that the introduction of a functional group such as 3-carbomethoxy reduces the duration of action by altering pharmacokinetic properties. SAR findings obtained by evaluating the neurotoxic effects of fentanyl analogs substituted in the position 3 of the piperidine ring parallel the SAR findings on analgesia in regard to potency and duration of action. This might suggest that similar receptors are involved in producing both antinociceptive and neurotoxic effects of these drugs. It appears that both the potency and the duration of action in the series of fentanyl analogs substituted in position 4 of the piperidine ring is influenced only by the steric requirement and not by the chemical nature of the substituent.

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.

Baseline temperature in an animal model of schizophrenia : Long-term effects of perinatal phencyclidine administration

Phencyclidine (PCP), a dissociative anaesthetic, acts as a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. PCP is a psychostimulant capable of producing both positive and negative symptoms of schizophrenia, including cognitive dysfunction in normal humans. Perinatal phencyclidine administration to rats has been widely accepted as an animal model of schizophrenia. It has been known for a long time that schizophrenia patients may develop various thermoregulatory disturbances. The aim of this study was to assess the acute effects of phencyclidine administration on the temperature of newborn rats, the long-term effects on the baseline temperature of perinatal phencyclidine administration and the effects of a PCP challenge on the temperature of adult perinatally treated rats. The animals were treated on the 2nd, 6th, 9th and 12th postnatal (PN) days with either phencyclidine (10 mg/kg) or saline. The interscapular skin temperature was measured during the first 40 postnatal days and subsequently the colonic temperature until PN day 62. The immediate effect of phencyclidine administration to pups was a significant decrease of the body temperature, while the application of PCP to adult rats perinatally treated with either saline or PCP caused a significant increase of the baseline temperature. Perinatal phencyclidine administration to rat pups produced a long lasting effect on the baseline temperature. It can be concluded that the nature of the response to acute phencyclidine administration differs between newborn and adult rats. Further experiments are necessary in order to clarify the role of specific neurotransmitter systems in the changes of temperature regulation provoked by phencyclidine administration.

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.

The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: The role of NO/cGMP/K+ATP pathway

Abstract Context: Magnesium and MK-801 (dizocilpine), antagonists of N-methyl-d-aspartate receptors, are involved in the processing of pain. Objective: This study determines whether magnesium sulfate (MS) and MK-801 affects visceral inflammatory pain and determines a possible mechanism of action. Materials and methods: Analgesic activity was assessed using the acetic acid-induced writhing test in rats. MS (1–45 mg/kg) or MK-801 (0.005–0.03 mg/kg) was administrated subcutaneously (s.c.). To assess possible mechanisms of action, we examined the effects of l-NAME (10 mg/kg, intraperitoneal), methylene blue (0.5 mg/kg, s.c.), and glibenclamide (3 mg/kg, s.c.) on the effect of MS or MK-801. Results: MS and MK-801 showed biphasic and linear dose–response pattern, respectively. MS reduces the number of writhing on the dose of 1, 5, and 15 mg/kg by 60, 50, and 78%, respectively, while it has no effects on the doses of 30 and 45 mg/kg. MK-801 (0.005–0.03 mg/kg) showed decrease in the number of writhing by 33–79%. The mean effective doses of MS and MK-801 were 6.6 (first phase) and 0.009 mg/kg, respectively. Both drugs did not impair the rotarod performance. l-NAME, methylene blue, and glybenclamide reduced the effect of MK-801 by 100, 43, and 64%, respectively, but not the effect of MS. Conclusions: The results suggest that MS and MK-801 may be useful analgesics in the management of visceral inflammatory pain, at doses that do not induce motor impairment. The modulation of NO/cGMP/K+ATP pathway plays an important role in the antinociceptive mechanism of MK-801, but does not contribute to the antinociceptive effect of MS.

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

This study investigated whether systemic magnesium sulfate (an antagonist at the glutamate subtype of N-methyl-D-aspartate receptor) affects inflammatory pain, and whether the nitric oxide pathway is involved. Carrageenan (0.5%, 0.1 mL, intraplantar)-induced mechanical hyperalgesia was evaluated using the electronic von Frey test in male Wistar rats. Magnesium sulfate had no effect when injected locally into the inflamed rat paw. However, subcutaneous magnesium sulfate, at doses of 0.5, 5, 15 and 30 mg/kg, reduced the hyperalgesia by 44.4 ± 8.8, 68 ± 8.4, 24.6 ± 6.9 and 45.3 ± 6.7% respectively. N-nitro-L-arginine methyl ester hydrochloride (L-NAME) (3 and 5 mg/kg, intraperitoneal), a non-selective nitric oxide synthase inhibitor, significantly reduced the effects of magnesium sulfate. Also, L-arginine (0.4 mg/kg, subcutaneously) significantly reversed the effect of L-NAME in the magnesium sulfate-treated rats. A selective inhibitor of neuronal or inducible nitric oxide synthase, N-ω-Propyl-L-arginine hydrochloride (L-NPA) (0.5, 1 and 2 mg/kg, intraperitoneal) and S-methylisothiourea (SMT) (0.005, 0.01 and 0.015 mg/kg, intraperitoneal) reduced the effect of magnesium sulfate significantly only at the highest doses tested. When given alone, L-NAME (3 and 5 mg/kg) L-NPA (2 mg/kg) and SMT (0.015 mg/kg) did not have any influence on carrageenan-induced hyperalgesia. The present study revealed that magnesium sulfate is effective against inflammatory pain after systemic, but not after local peripheral administration, and activation of the nitric oxide pathway is probably involved in the anti-hyperalgesic effect of magnesium sulfate. Low doses of systemic magnesium sulfate given as a pretreatment or a treatment might have a beneficial effect in patients with inflammatory somatic pain.