Povezanost centralnog glutamatnog sustava s antinociceptivnim učinkom botulinum toksina tipa A

master's thesis

• Title (english): Involvement of central glutamate system in antinociceptive effect of botulinum toxin type A
• Author: Luciano Blažević
• Mentor: Lidija Bach-Rojecky (mentor)
• Committee member: Lidija Bach-Rojecky (predsjednik povjerenstva)
• Committee member: Živka Juričić (član povjerenstva)
• Committee member: Jasna Jablan (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of pharmacology); Zagreb
• Defense date and country: 2017-04-13, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Kliničke studije pokazuju da jednokratno lokalno primijenjen BT-A smanjuje bol tijekom nekoliko mjeseci. Nadalje, brojna eksperimentalna istraživanja ukazuju da primjena botulinum toksina smanjuje lučenje glutamata iz perifernih završetaka primarnih aferentnih neurona. Budući da je glutamat najvažniji ekscitacijski neurotransmitor u nociceptivnom putu, moguće je da BT-A inhibira lučenje glutamata i u središnjim sinapsama.
Hipoteza ovog istraživanja je da BT-A povećava analgetski učinak niskih doza antagonista glutamata interakcijom na razini kralješničke moždine.
Ispitivanja su provedena na mužjacima štakora soja Wistar. BT-A (5 i.j./kg) je primijenjen intraplanarno, a kompetitivni antagonist NMDA receptora 2-amino-5-fosfonopentanoična kiselina (AP5 u dozama 1, 5 i 10 g/10l) intratekalno. Antinociceptivno djelovanje je ispitivano u formalinskom testu.
AP5 je smanjio bolni odgovor uzrokovan formalinom u prvoj-akutnoj i drugoj-upalnoj fazi, dok je BT-A smanjio samo upalnu fazu formalinskog testa. Kombinacijom BT-A i AP5 postignut je sinergistički učinak u smanjenju boli u obje faze testa.
Dobiveni rezultati ukazuju na interakciju između BT-A i glutamatnog sustava u procesu nocicepcije čime se otvara novo područje istraživanja koje bi moglo ponuditi odgovore na pitanja o još uvijek nejasnom mehanizmu antinociceptivvnog djelovanja BT-A.
Potencijalni sinergizam između BT-A i niskih, ali sigurnih doza NMDA antagonista mogao bi utjecati na dizajniranje kliničkih studija kako bi se ispitala djelotvornost i sigurnost ovakvih kombinacija u ljudi.

Abstract (english)

Clinical studies have shown that BT-A decreases pain for several months after single local injection. In addition, numerous researches suggest that peripheral application of BT-A decreases glutamate release from peripheral endings of primary afferent neurons. Due to a fact that glutamate is the most important excitatory neurotransmitter in nociceptive pathways, it is possible that BT-A inhibits glutamate release in central synapses. Hypothesis of this research is that BT-A increases analgesic effect of low doses of glutamate antagonists at spinal cord level. Male Wistar rats were injected subcutaneously into the rat hindpaw with BT-A(5 i.j./kg). Competetive NMDA antagonist 2-amino-5-phosphonopentanoate (AP5 in doses 1, 5, 10 l/ 10 l) was administered intrathecally. Antinociceptive effect was examined with formalin test. AP5 reduced pain response in first-acute and second-inflammatory phase of formalin test, while BT-A reduced pain response only in second phase of formalin test. Synergistic effect in pain response reduction was observed in a group that was given BT-A and AP5. Results of this work indicate interaction between BT-A and central glutamate system in nociception process, which opens a new area for future researches that could provide answers for still unknown mechanism of antinociceptive effect of BT-A. Potential synergism between BT-A and smaller, but safer doses of NMDA antagonists could have impact on design of clinical studies that would evaluate efficacy and safety of these combinations in humans.

• Keywords: botulinum toksin; glutamat; antagonist NMDA receptora; bol; formalinski test
• Keywords (english): botulinum toxin; glutamate; NMDA receptor antagonist; pain; formalin test
• Language: croatian
• URN:NBN: urn:nbn:hr:163:992765
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-04-20 13:49:47