Antinociceptivni efekat, mehanizam dejstva i interakcije levetiracetama u modelima somatskog, visceralnog i neuropatskog bola

Abstract

Svrha studije: Levetiracetam, antiepileptik novije generacije, ostvaruje antinociceptivno dejstvou nekim animalnim modelima bola. Cilj našeg rada bio je da se ispita: 1) antinociceptivni efekatlevetiracetama u somatskom (inflamatornom), visceralnom i neuropatskom modelu bola, 2)mehanizam antinociceptivnog efekta levetiracetama u inflamatornom modelu bola, 3) efekatkombinovane primene levetiracetama i standardnih/alternativnih analgetika u inflamatornom,visceralnom i neuropatskom modelu bola i 4) uticaj antinociceptivnih doza levetiracetama namotornu spretnost eksperimentalnih životinja.Metode: Kao model inflamatornog bola korišćen je model inflamatorne hiperalgezije izazvanekarageninom u pacova. Hiperalgezija i efekti lekova/kombinacija lekova mereni su umodifikovanom testu pritiska na šapu pacova. U ovom modelu bola ispitan je i mehanizamantinociceptivnog dejstva levetiracetama, ispitivanjem uticaja levetiracetama na GABAAergičke,opioidergičke, α2-adrenergičke, serotonergičke i adenozinske receptore, nakon sistemskei lokalne periferne primene levetiracetama i odgovarajućih antagonista. U testu grčeva u miševaizazvanih sirćetnom kiselinom, model visceralnog bola, ispitivani su efekti lekova/kombinacijalekova. Kao model neuropatskog bola korišćen je model dijabetesne neuropatije u miševa.Dijabetes je izazivan streptozotocinom, a hiperalgezija i efekti lekova/kombinacija lekovamereni su u testu izmicanja repa pod uticajem toplote. Rotarod test korišćen je za procenu uticajaantinociceptivnih doza levetiracetama na motornu spretnost miševa i pacova.Rezultati: U inflamatornom modelu bola u pacova: 1) levetiracetam je ostvario dozno-zavisnoantihiperalgezijsko dejstvo nakon sistemske i lokalne periferne primene, 2) antagonisti GABAA,opioidergičkih, α2-adrenergičkih, serotonergičkih i adenozinskih receptora inhibirali suantihiperalgezijsko dejstvo levetiracetama, 3) levetiracetama primenjen u kombinaciji saibuprofenom/celekoksibom/paracetamolom/ceftriaksonom/kofeinom ostvario je sinergističkuinterakciju. U visceralnom modelu bola u miševa, levetiracetam je ostvario dozno-zavisnoantinociceptivno dejstvo i sinergističku interakciju sa paracetamolom i ceftriaksonom. U modeludijabetesne neuropatije u miševa levetiracetam je ispoljio antinociceptivno dejstvo na dozno zavisan način i sinergizam sa ibuprofenom, paracetamolom, gabapentinom, duloksetinom i alfalipoinskomkiselinom...

Background and aim: Levetiracetam, a novel antiepileptic drug, exerts antinociceptive effectsin some animal pain models. The aim of our study was to investigate: 1) the antinociceptiveeffects 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) theeffects of two-drug combinations of levetiracetam with standard/alternative analgesics in theinflammatory, visceral and neuropathic pain models, and 4) the influence of levetiracetam’santinociceptive doses on motor performance in experimental animals.Methods: The inflammatory hyperalgesia induced by carrageenan in rats was used as a model ofinflammatory pain. Hyperalgesia and drug/drug combinations effects were examined by amodified paw pressure test. In this pain model, levetiracetam's mechanism of action wasevaluated by examining the influence of levetiracetam on GABAA-ergic, opioidergic, α2-adrenergic, serotonergic and adenosine receptors, after systemic and local peripheraladministration of levetiracetam and corresponding antagonists. In the acetic acid-inducedwrithing 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 diabeteswas induced by streptozotocine and the hyperalgesia and drug/drug combinations effects wereassessed by the radiant heat tail flick test. Rotarod test was used to evaluate the influence ofantinociceptive doses of levetiracetam on motor performance in both rats and mice.Results: In the inflammatory pain model in rats: 1) levetiracetam exerted dose-dependentantihyperalgesic effects after sistemic and local peripheral administration, 2) the antagonists ofGABAA-ergic, opioidergic, α2-adrenergic, serotonergic and adenosine receptors inhibited theantihyperalgesic effects of levetiracetam, 3) levetiracetam exerted synergistic interactions withibuprofen/celecoxib/paracetamol/ceftriaxone/caffeine. In the visceral pain model in mice,levetiracetam exerted dose-dependent antinociceptive effects and synergistic interactions withparacetamol and ceftriaxone. In the model of diabetic neuropathy in mice, levetiracetam exertedantinociceptive effects, in a dose-dependent manner, and synergistic interactions with ibuprofen,paracetamol, gabapentin, duloxetine and alfa-lipoic acid...