Magnesium sulfate reduces formalin-induced orofacial pain in rats with normal magnesium serum levels.

BACKGROUND: In humans, orofacial pain has a high prevalence and is often difficult to treat. Magnesium is an essential element in biological a system which controls the activity of many ion channels, neurotransmitters and enzymes. Magnesium produces an antinociceptive effect in neuropathic pain, while in inflammatory pain results are not consistent. We examined the effects of magnesium sulfate using the rat orofacial formalin test, a model of trigeminal pain. METHODS: Male Wistar rats were injected with 1.5% formalin into the perinasal area, and the total time spent in pain-related behavior (face rubbing) was quantified. We also spectrophotometrically determined the concentration of magnesium and creatine kinase activity in blood serum. RESULTS: Magnesium sulfate administered subcutaneously (0.005-45mg/kg) produced significant antinociception in the second phase of the orofacial formalin test in rats at physiological serum concentration of magnesium. The effect was not dose-dependent. The maximum antinociceptive effect of magnesium sulfate was about 50% and was achieved at doses of 15 and 45mg/kg. Magnesium did not affect increase the levels of serum creatine kinase activity. CONCLUSIONS: Preemptive systemic administration of magnesium sulfate as the only drug can be used to prevent inflammatory pain in the orofacial region. Its analgesic effect is not associated with magnesium deficiency.

Cardiac Arrhythmias in Patients with Chronic Kidney Disease: Implications of Renal Failure for Antiarrhythmic Drug Therapy.

The kidney has numerous complex interactions with the heart, including shared risk factors (e.g., hypertension, dyslipidemia, etc.) and mutual amplification of morbidity and mortality. Both cardiovascular diseases and chronic kidney disease (CKD) may cause various alterations in cardiovascular system, metabolic homeostasis and autonomic nervous system that may facilitate the occurrence of cardiac arrhythmias. Also, pre-existent or incident cardiac arrhythmias such as atrial fibrillation (AF) may accelerate the progression of CKD. Patients with CKD may experience various cardiac rhythm disturbances including sudden cardiac death. Contemporary management of cardiac arrhythmias includes the use of antiarrhythmic drugs (AADs), catheter ablation and cardiac implantable electronic devices (CIEDs). Importantly, AADs are not used only as the principal treatment strategy, but also as an adjunct therapy in combination with CIEDs, to facilitate their effects or to minimize inappropriate device activation in selected patients. Along with their principal antiarrhythmic effect, AADs may also induce cardiac arrhythmias and the risk for such proarrhythmic effect(s) is particularly increased in patients with reduced left ventricular systolic function or in the setting of electrolyte imbalance. Moreover, CKD itself can induce profound alterations in the pharmacokinetics and pharmacodynamics of many drugs including AADs, thus facilitating the drug accumulation and increased exposure. Hence, the use of AADs in patients with CKD may be challenging. In this review article, we provide an overview of the characteristics of arrhythmogenesis in patients with CKD with special emphasis on the complexity of pharmacokinetics and risk for proarrhythmias when using AADs in patients with cardiac arrhythmias and CKD.

Incidence, predictors and prognostic implications of bleeding complicating primary percutaneous coronary intervention.

BACKGROUND/AIM: Data about bleeding complicating primary percutaneous coronary intervention (PCI) are more frequently obtained from randomized clinical trials on patients with acute coronary syndromes (ACS), but less frequently from surveys or registries on patients with ST-elevation myocardial infarction (STEMI). The aim of this study was to investigate the incidence, predictors and prognostic impact of in-hospital major bleeding in the population of unselected real-world patients with acute STEMI undergoing primary PCI. METHODS: All consecutive patients presenting with STEMI who underwent primary PCI at a single large tertiary healthcare center between January 2005 and July 2009, were studied. Major bleeding was defined according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) study criteria. We examined the association between in-hospital major bleeding and death or major adverse cardiac events (MACE) in patients treated with PCI. The primary outcomes were in-hospital and 6-month mortality and MACE. RESULTS: Of the 770 STEMI patients treated with primary PCI, in-hospital major bleeding occurred in 32 (4.2%) patients. Independent pre-dictors of major bleeding were advanced age (≥ 65 years), female gender, baseline anemia and elevated white blood cell (WBC) count and signs of congestive heart failure at admission (Killip class II-IV). In-hospital and 6 month mortality and MACE, rates were more than 2.5-fold-higher in patients who developed major bleeding compared with those who did not. Major bleeding was predictor of 6-month MACE, independent of a few risk factors (previous MI, previous PCI, diabetes mellitus and hypertension); (OR = 3.02; 95% CI for OR 1.20-7.61; p = 0.019) but was not a true independent predictor of MACE and mortality in the fully adjusted models. CONCLUSION: Patients of advanced age, female gender, with baseline anemia and elevated WBC count and those with Killip class II-IV at presentation are at particularly high risk of bleeding after primary PCI. Bleeding is associated with adverse outcome and may be an important marker of patient frailty, but it is not a true independent predictor of mortality/MACE.

TRPA1, NMDA receptors and nitric oxide mediate mechanical hyperalgesia induced by local injection of magnesium sulfate into the rat hind paw.

Previous studies have shown that while magnesium, an antagonist of the glutamate subtype of N-methyl-D-aspartate receptors, possesses analgesic properties, it can induce writhing in rodents. The aim of this study was to determine the effect and mechanism of action of local (intraplantar) administration of magnesium sulfate (MS) on the paw withdrawal threshold (PWT) to mechanical stimuli. The PWT was evaluated by the electronic von Frey test in male Wistar rats. Tested drugs were either co-administered intraplantarly (i.pl.) with MS or given into the contralateral paw to exclude systemic effects. MS at doses of 0.5, 1.5, 3 and 6.2 mg/paw (i.pl.) induced a statistically significant (as compared to 0.9% NaCl) and dose-dependent mechanical hyperalgesia. Only isotonic MS (250 mmol/l or 6.2% or 6.2 mg/paw) induced mechanical hyperalgesia that lasted at least six hours. Isotonic MS-induced mechanical hyperalgesia was reduced in a dose-dependent manner by co-injection of camphor, a non-selective TRPA1 antagonist (0.3, 1 and 2.5 µg/paw), MK-801, a NMDA receptor antagonist (0.001, 0.025 and 0.1 µg/paw), L-NAME, a non-selective nitric oxide (NO) synthase inhibitor (20, 50 and 100 µg/paw), ARL 17477, a selective neuronal NOS inhibitor (5.7 and 17 µg/paw), SMT, a selective inducible NOS inhibitor (1 and 2.78 µg/paw), and methylene blue, a guanylate cyclase inhibitor (5, 20 and 125 µg/paw). Drugs injected into the contralateral hind paw did not produce significant effects. These results suggest that an i.pl. injection of MS produces local peripheral mechanical hyperalgesia via activation of peripheral TRPA1 and NMDA receptors and peripheral production of NO.

Nitric oxide synthase modulates the antihyperalgesic effect of the NMDA receptor antagonist MK-801 on Carrageenan-induced inflammatory pain in rats.

The N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor, may play a significant role in the development and maintenance of an inflammatory pain. Activation of NMDA receptors may cause nitric oxide (NO) release through activation of NO synthase (NOS). MK-801, a noncompetitive NMDA receptor antagonist is commonly used as a neuropharmacological tool. The interaction between MK-801 and NOS in the inflammatory pain has not been evaluated before. We investigated whether MK-801 affects inflammatory pain and whether NOS modulates the effect of MK-801. Carrageenan-induced hyperalgesia was evaluated by measuring the withdrawal response to mechanical stimuli, using an electronic version of the von Frey anesthesiometer in Wistar rats. MK-801 given subcutaneously (0.5-20 µg/kg) or intraplantarly (0.1 and 0.15 µg/paw) significantly reduced mechanical hyperalgesia. Intraplantarly given MK-801 exerted a local antihyperalgesic effect, because when applied to the contralateral side it did not reduce mechanical sensitivity in the ipsilateral side. N-nitro-L-arginine methyl ester hydrochloride (5 and 10 mg/kg), a non-selective NOS inhibitor, significantly reduced the effects of MK-801. N-ω-Propyl-L-arginine hydrochloride (0.5-2 mg/kg), a selective inhibitor of neuronal NOS, increased the antihyperalgesic effect of MK-801, whereas S-methylisothiourea (5-15 µg/kg), a selective inhibitor of inducible NOS, lowered the antihyperalgesic effect of MK-801. Importantly, each NOS inhibitor given alone did not affect carrageenan-induced hyperalgesia. In conclusion, MK-801 is effective against inflammatory pain and its antihyperalgesic effect is modulated in a different ways by NOS, being enhanced by a neuronal NOS inhibitor but reduced by an inducible NOS inhibitor.

Synergistic interaction between ketamine and magnesium in lowering body temperature in rats.

A large body of evidence supports the existence of an endogenous glutamate system that tonically modulates body temperature via N-methyl-d-aspartate (NMDA) receptors. Ketamine and magnesium, both NMDA receptor antagonists, are known for their anesthetic, analgesic and anti-shivering properties. This study is aimed at evaluating the effects of ketamine and magnesium sulfate on body temperature in rats, and to determine the type of interaction between them. The body temperature was measured by insertion of a thermometer probe 5cm into the colon of unrestrained male Wistar rats (200-250g). Magnesium sulfate (5 and 60mg/kg, sc) showed influence neither on baseline, nor on morphine-evoked hyperthermic response. Subanesthetic doses of ketamine (5-30mg/kg, ip) given alone, produced significant dose-dependent reduction in both baseline colonic temperature and morphine-induced hyperthermia. Analysis of the log dose-response curves for the effects of ketamine and ketamine-magnesium sulfate combination on the baseline body temperature revealed synergistic interaction, and about 5.3 fold reduction in dosage of ketamine when the drugs were applied in fixed ratio (1:1) combinations. In addition, fixed low dose of magnesium sulfate (5mg/kg, sc) enhanced the temperature lowering effect of ketamine (1.25-10mg/kg, ip) on baseline body temperature and morphine-induced hyperthermia by factors of about 2.5 and 5.3, respectively. This study is the first to demonstrate the synergistic interaction between magnesium sulfate and ketamine in a whole animal study and its statistical confirmation. It is possible that the synergy between ketamine and magnesium may have clinical relevance.

Novel oral anticoagulants for stroke prevention in atrial fibrillation: focus on apixaban.

Stroke prevention in atrial fibrillation (AF) has been challenging over decades, mostly due to a number of difficulties associated with oral vitamin K antagonists (VKAs), which have been the most effective stroke prevention treatment for a long time. The oral direct thrombin inhibitors (e.g., dabigatran) and oral direct inhibitors of factor Xa (e.g., rivaroxaban, apixaban) have emerged recently as an alternative to VKAs for stroke prevention in AF. These drugs act rapidly, and have a predictable and stable dose-related anticoagulant effect with a few clinically relevant drug-drug interactions. The novel oral anticoagulants are used in fixed doses with no need for regular laboratory monitoring of anticoagulation intensity. However, each of these drugs has distinct pharmacological properties that could influence optimal use in clinical practice. The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban. Moreover, the Apixaban Versus Acetylsalicylic Acid to prevent Strokes (AVERROES) trial included patients with AF who have failed or were unsuitable for warfarin, and compared apixaban versus aspirin for stroke prevention in AF. Overall, apixaban has two large trials for stroke prevention in AF showing benefits not only over warfarin, but also over aspirin among those patients who have failed or refused warfarin. In the ARISTOTLE trial, apixaban was superior to warfarin in the reduction of stroke or systemic embolism, major bleeding, intracranial hemorrhage, and all-cause mortality, with a similar reduction in the rate of ischemic stroke and better tolerability. When compared with aspirin in the AVERROES trial, apixaban was associated with more effective reduction of stroke, a similar risk of major bleeding, and better tolerability. In this review article, the authors summarize the current knowledge on novel oral anticoagulants and discuss the clinical aspects of their use for stroke prevention in AF, with particular emphasis on apixaban.

Reliable identification of "truly low" thromboembolic risk in patients initially diagnosed with "lone" atrial fibrillation: the Belgrade atrial fibrillation study.

BACKGROUND: The CHA(2)DS(2)-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, previous Stroke/transient ischemic attack [TIA], Vascular disease, Age 65-74 years, and Sex category [female gender]) schema recently has been introduced to complement the CHADS(2) (Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and previous stroke or TIA) score and improve the identification of atrial fibrillation (AF) patients at "truly low risk" for thromboembolism. We tested the predictive ability of the CHA(2)DS(2)-VASc, CHADS(2), and van Walraven risk stratification schemes in a cohort of "lone" AF patients with a 12-year follow-up. METHODS AND RESULTS: We conducted a registry-based, observational cohort study of 345 patients initially diagnosed with "lone" AF between 1992 and 2007. At baseline, all patients had the CHADS(2) and van Walraven scores of 0, and 262 (75.9%) had a CHA(2)DS(2)-VASc score of 0. During follow-up (or within a year prior to stroke), 228 (66.1%), 234 (67.8%), and 150 patients (43.5%) retained the CHADS(2), van Walraven, and CHA(2)DS(2)-VASc scores of 0, respectively. The overall rate of ischemic stroke was 0.19 (95% CI: 0.18-0.20) per 100 patient years. In the multivariable analysis, only the CHA(2)DS(2)-VASc score of 0 was significantly related to the absence of stroke (odds ratio 5.1, 95% CI: 1.5-16.8, P=0.008). Only the CHA(2)DS(2)-VASc score had a significant prediction ability (c-statistic 0.72 [0.61-0.84], P=0.031). CONCLUSIONS: The CHA(2)DS(2)-VASc score reliably identified the "lone" AF patients who were at "truly low risk" for thromboembolism, and was the only tested risk stratification scheme with a significant predictive ability for thromboembolism among lone AF patients.

Pharmacological interaction between oxcarbazepine and two COX inhibitors in a rat model of inflammatory hyperalgesia.

Oxcarbazepine, ibuprofen and etodolac have efficacy in inflammatory pain. The combination of different drugs activates both central and peripheral pain inhibitory pathways to induce additive or synergistic antinociception, and this interaction may allow lower doses of each drug combined and improve the safety profile, with lower side-effects. This study aimed to examine the effects of oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations, in a rat model of inflammatory hyperalgesia, and determine the type of interaction between drugs. Rats were intraplantarly injected with carrageenan (0.1 ml, 1%) and the hyperalgesia was assessed by modified paw pressure test. The anti-hyperalgesic effects of oxcarbazepine, ibuprofen and etodolac and oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations were examined. Drugs were co-administered in a fixed-dose fractions of the ED50 and the type of interaction was determined by isobolographic analysis. Oxcarbazepine (40-160 mg/kg; p.o.), ibuprofen (10-120 mg/kg; p.o.) and etodolac (5-20 mg/kg; p.o.) produced a significant, dose-dependent anti-hyperalgesia in carrageenan-injected rats. ED50 values (mean±SEM) for oxcarbazepine, ibuprofen and etodolac were 88.17±3.65, 47.07±10.27 and 13.05±1.42 mg/kg, respectively. Oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations induced significant and dose-dependent anti-hyperalgesia. Isobolographic analysis revealed that oxcarbazepine exerts a synergistic interaction with ibuprofen, with almost 4-fold reduction of doses of both drugs in combination. In contrast, there was an additive interaction with etodolac. Synergistic interaction of oxcarbazepine with ibuprofen and its additive interaction with etodolac provide new information about the combination pain treatment and could be explored further in patients with inflammatory pain. Adverse effect analysis of the combinations is necessary to verify possible clinical use of the mixtures.

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 (ED(50)), 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 ED(50)) 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 ED(50)) 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 ED(50). 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.

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.

Study of molecular and granular layer of dentate gyrus of female rats neonatally treated with estrogen.

The proliferation of hippocampal dentate gyrus granule cells was investigated using (3)H-thymidine incorporation in control and estrogen-treated rats. Newborn 3-day old female Wistar rats were treated with a single dose of 1 mg of estradiol and 30 microCi (3)H-thymidine, and were sacrificed when 10 days old. The total number of neurons and the number of labeled granule cells in the granular layer and its subdivisions of both suprapyramidal and infrapyramidal limbs were analyzed using a stereological method. In both limbs, the total number of neurons as well as the total number of labeled granule cells in the granular layer were significantly increased in treated rats compared to corresponding controls. The thicknesses of the molecular and the granular layers and their subdivisions of both suprapyramidal and infrapyramidal limbs were analyzed using a stereological method. In treated female rats the molecular layer (ML) in both limbs was significantly decreased, and the granular layer (GL) was significantly increased in suprapyramidal limb. However, in the infrapyramidal limb an increased number of labeled cells in treated animals were significant in all particular zones of the granular layer. In the suprapyramidal limb's granular layer a significant increase in labeled cells was observed in subgranular zone (SGZ). Our results suggest a differential effect of estradiol on thicknesses of the ML and the GL, and dentate gyrus granule cells proliferation through the early rat life.

Butyrylcholinesterase activity and mortality risk in hemodialysis patients: comparison to hsCRP and albumin.

OBJECTIVE: To test the prediction power of butyrylcholinesterase (BuChE) activity for mortality risk in hemodialysis patients during 12 months follow-up, and made comparison to hsCRP and albumin. MATERIALS AND METHODS: The study enrolled 62 patients, aged 31-79 years. Serum BuChE, high-sensitivity C-reactive protein (hsCRP) and albumin were measured after 1, 3, 9 and 12 months of dialysis. The Kaplan-Meier survival curves were employed in mortality prediction. RESULTS: BuChE was positively associated with serum albumin (r=0.318; p=0.012) and inversely related to hsCRP (r=-0.358; p=0.004). The highest mortality was in the lowest quartile of basal albumin (<38.4 g/L; p=0.027), hsCRP concentrations >8 mg/L (p=0.005), and BuChE activity in the lowest tercile of basal values (<5.92 kU/L; p=0.0041). CONCLUSION: Our results suggest that low BuChE activity may be a nonspecific risk factor for mortality in patients who are on hemodialysis.

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 TD(50)/writhing ED(50)) 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.

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 (GABA(A) 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 GABA(A) receptor activation.

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.

The involvement of peripheral alpha 2-adrenoceptors in the antihyperalgesic effect of oxcarbazepine in a rat model of inflammatory pain.

BACKGROUND: We studied whether peripheral alpha2-adrenergic receptors are involved in the antihyperalgesic effects of oxcarbazepine by examining the effects of yohimbine (selective alpha2-adrenoceptor antagonist), BRL 44408 (selective alpha(2A)-adrenoceptor antagonist), MK-912 (selective alpha2C-adrenoceptor antagonist), and clonidine (alpha2-adrenoceptor agonist) on the antihyperalgesic effect of oxcarbazepine in the rat model of inflammatory pain. 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 oxcarbazepine (i.pl.) on Con A-induced hyperalgesia; and 3) the effects of i.pl. yohimbine, BRL 44408, MK-912 and clonidine on the oxcarbazepine antihyperalgesia. RESULTS: Both oxcarbazepine (1000-3000 nmol/paw; i.pl.) and clonidine (1.9-7.5 nmol/paw; i.pl.) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by Con A. Yohimbine (260 and 520 nmol/paw; i.pl.), BRL 44408 (100 and 200 nmol/paw; i.pl.) and MK-912 (10 and 20 nmol/paw; i.pl.) significantly depressed the antihyperalgesic effects of oxcarbazepine (2000 nmol/paw; i.pl.) in a dose-dependent manner. The effects of antagonists were due to local effects since they were not observed after administration into the contralateral hindpaw. Oxcarbazepine and clonidine administered jointly in fixed-dose fractions of the ED(50) (1/4, 1/2, and 3/4) caused significant and dose-dependent reduction of hyperalgesia induced by Con A. Isobolographic analysis revealed an additive antihyperalgesic effect. CONCLUSIONS: Our results indicate that the peripheral alpha2A and alpha2C adrenoceptors could be involved in the antihyperalgesic effects of oxcarbazepine in a rat model of inflammatory hyperalgesia.

The effects of alpha2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain.

In this study, the effects of yohimbine (alpha2-adrenoceptor antagonist) and clonidine (alpha2-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 alpha2-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 anti-hyperalgesic effects of carbamazepine and oxcarbazepine are attenuated by treatment with adenosine receptor antagonists.

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 (5-20mg/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 A(1) 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 A(1) 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.