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

Abstract

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...