Antinociceptive effect, mechanism of action and interactions of levetiracetam in somatic, visceral and neuropathic pain models

Svrha studije: Levetiracetam, antiepileptik novije generacije, ostvaruje antinociceptivno dejstvo u nekim animalnim modelima bola. Cilj našeg rada bio je da se ispita: 1) antinociceptivni efekat levetiracetama u somatskom (inflamatornom), visceralnom i neuropatskom modelu bola, 2) mehanizam antinociceptivnog efekta levetiracetama u inflamatornom modelu bola, 3) efekat kombinovane primene levetiracetama i standardnih/alternativnih analgetika u inflamatornom, visceralnom i neuropatskom modelu bola i 4) uticaj antinociceptivnih doza levetiracetama na motornu spretnost eksperimentalnih životinja. Metode: Kao model inflamatornog bola korišćen je model inflamatorne hiperalgezije izazvane karageninom u pacova. Hiperalgezija i efekti lekova/kombinacija lekova mereni su u modifikovanom testu pritiska na šapu pacova. U ovom modelu bola ispitan je i mehanizam antinociceptivnog dejstva levetiracetama, ispitivanjem uticaja levetiracetama na GABAAergičke, opioidergičke, α2-adrenergičke, serotonergičke i adenozinske receptore, nakon sistemske i lokalne periferne primene levetiracetama i odgovarajućih antagonista. U testu grčeva u miševa izazvanih sirćetnom kiselinom, model visceralnog bola, ispitivani su efekti lekova/kombinacija lekova. Kao model neuropatskog bola korišćen je model dijabetesne neuropatije u miševa. Dijabetes je izazivan streptozotocinom, a hiperalgezija i efekti lekova/kombinacija lekova mereni su u testu izmicanja repa pod uticajem toplote. Rotarod test korišćen je za procenu uticaja antinociceptivnih doza levetiracetama na motornu spretnost miševa i pacova. Rezultati: U inflamatornom modelu bola u pacova: 1) levetiracetam je ostvario dozno-zavisno antihiperalgezijsko dejstvo nakon sistemske i lokalne periferne primene, 2) antagonisti GABAA, opioidergičkih, α2-adrenergičkih, serotonergičkih i adenozinskih receptora inhibirali su antihiperalgezijsko dejstvo levetiracetama, 3) levetiracetama primenjen u kombinaciji sa ibuprofenom/celekoksibom/paracetamolom/ceftriaksonom/kofeinom ostvario je sinergističku interakciju. U visceralnom modelu bola u miševa, levetiracetam je ostvario dozno-zavisno antinociceptivno dejstvo i sinergističku interakciju sa paracetamolom i ceftriaksonom. U modelu dijabetesne neuropatije u miševa levetiracetam je ispoljio antinociceptivno dejstvo na dozno zavisan način i sinergizam sa ibuprofenom, paracetamolom, gabapentinom, duloksetinom i alfalipoinskom kiselinom...Background and aim: Levetiracetam, a novel antiepileptic drug, exerts antinociceptive effects in some animal pain models. The aim of our study was to investigate: 1) the antinociceptive effects of levetiracetam in the somatic (inflammatory), visceral and neuropathic pain models, 2) the mechanism of levetiracetam’s antinociceptive effect in the inflammatory pain model, 3) the effects of two-drug combinations of levetiracetam with standard/alternative analgesics in the inflammatory, visceral and neuropathic pain models, and 4) the influence of levetiracetam’s antinociceptive doses on motor performance in experimental animals. Methods: The inflammatory hyperalgesia induced by carrageenan in rats was used as a model of inflammatory pain. Hyperalgesia and drug/drug combinations effects were examined by a modified paw pressure test. In this pain model, levetiracetam's mechanism of action was evaluated by examining the influence of levetiracetam on GABAA-ergic, opioidergic, α2- adrenergic, serotonergic and adenosine receptors, after systemic and local peripheral administration of levetiracetam and corresponding antagonists. In the acetic acid-induced writhing test in mice, model of visceral pain, drug/drug combinations effects were examined. The model of diabetic neuropathy in mice was used as a model of neuropathic pain. The diabetes was induced by streptozotocine and the hyperalgesia and drug/drug combinations effects were assessed by the radiant heat tail flick test. Rotarod test was used to evaluate the influence of antinociceptive doses of levetiracetam on motor performance in both rats and mice. Results: In the inflammatory pain model in rats: 1) levetiracetam exerted dose-dependent antihyperalgesic effects after sistemic and local peripheral administration, 2) the antagonists of GABAA-ergic, opioidergic, α2-adrenergic, serotonergic and adenosine receptors inhibited the antihyperalgesic effects of levetiracetam, 3) levetiracetam exerted synergistic interactions with ibuprofen/celecoxib/paracetamol/ceftriaxone/caffeine. In the visceral pain model in mice, levetiracetam exerted dose-dependent antinociceptive effects and synergistic interactions with paracetamol and ceftriaxone. In the model of diabetic neuropathy in mice, levetiracetam exerted antinociceptive effects, in a dose-dependent manner, and synergistic interactions with ibuprofen,paracetamol, gabapentin, duloxetine and alfa-lipoic acid..

Antiepileptic drugs as analgesics/adjuvants in inflammatory pain: current preclinical evidence

Inflammatory pain is the most common type of pain that is treated clinically. The use of currently available treatments (classic analgesics - NSAID5, paracetamol and opioids) is limited by insufficient efficacy and/or side effects/ tolerance development. Antiepileptic drugs (AEDs) are widely used in neuropathic pain treatment, but there is substantial preclinical evidence on their efficacy against inflammatory pain, too. In this review we focus on gabapentinoids (gabapentin and pregabalin) and dibenzazepine AEDs (carbamazepine, oxcarbazepine, and recently introduced eslicarbazepine acetate) and their potential for relieving inflammatory pain. In models of somatic, visceral and trigeminal inflammatory pain, that have a translational value for inflammatory conditions in locomotor system, viscera and head/face, AEDs have demonstrated analgesic activity. This activity was mostly consistent, dependent on the dose and largely independent on the site of inflammation and method of its induction, nociceptive stimuli, species, specific drug used, its route of administration and dosing schedule. AEDs exerted comparable efficacy with classic analgesics. Effective doses of AEDs are lower than toxic doses in animals and, when expressed as equivalent human doses, they are largely overlapping with AEDs doses already used in humans for treating epilepsy/neuropathic pain. The main mechanism of antinociceptive/antihyperalgesic action of gabapentinoids in inflammatory pain models seems to be alpha 2 delta-dependent suppression of voltage -gated calcium channels in primary sensory neurons that leads to reduced release of neurotransmitters in the spinal/medullar dorsal horn. The suppression of NMDA receptors via co-agonist binding site primarily at spinal sites, activation of various types of K+ channels at spinal and peripheral sites, and activation of noradrenergic and serotonergic descending pain modulatory pathways may also contribute. Inhibition of voltage -gated sodium channels along the pain pathway is probably the main mechanism of antinociceptive/antihyperalgesic effects of dibenzazepines. The recruitment of peripheral adrenergic and purinergic mechanisms and central GABAergic mechanisms may also contribute. When co-administered with classic/other alternative analgesics, AEDs exerted synergistic/additive interactions. Reviewed data could serve as a basis for clinical studies on the efficacy/safety of AEDs as analgesics/adjuvants in patients with inflammatory pain, and contribute to the improvement of the treatment of various inflammatory pain states

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 (150 mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10-40 mg/kg; p.o.) and oxcarbazepine (20-80 mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5-60 mg/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 close-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

Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery

Background/Aims: 5-Ketoximeisosorbide-2-mononitrate (50-IS-2-MN) was synthesized and its pharmacological and toxicological characteristics were examined and compared with its parent drug, isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7), and its diastereoisomer 2-ketoximeisosorbide-5-mononitrate. Methods: Vasorelaxation was studied on phenylephrine-precontracted rat superior mesenteric artery rings in organ bath procedure. In some rings, the endothelium was mechanically removed. In vitro tolerance was induced by treating the precontracted rings with maximal concentrations of the parent drug and the ketoximes, and after washing out, the procedure was repeated for two times. Furthermore, rats were treated with a single oral dose (1000 mg/kg) of 50-IS-2-MN and 20-IS-5-MN. Results: After a phenylephrine-induced contraction, 50-IS-2-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation of the rat superior mesenteric artery that was strongly potentiated after the removal of the vascular endothelium. In preparations with or without endothelium, 50-IS-2-MN was a more potent relaxant than either the parent compound or its isomer. The mechanism of the relaxant effect of 50-IS-2-MN involves the activated soluble guanylyl cyclase-cyclic GMP pathway. Hydralazine (10(-5) mol/l), a strong antioxidant, ameliorated tolerance to IS-5-MN, but did not affect the absence of tolerance to either ketoxime. The minimum lethal dose in rat for 50-IS-2-MN and 20-IS-5-MN was greater than 1000 mg/kg. Conclusion: These results suggest that the modification of the configuration at the ester carbon of IS-5-MN contributes to more potent and tolerance-devoid activity on the rat superior mesenteric artery