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Analiza Efektu Przeciwbólowego Nowych Analogów Neuropeptydów W Mysim Modelu Bólu Nowotworowego

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Analiza Efektu Przeciwbólowego Nowych Analogów Neuropeptydów W Mysim Modelu Bólu Nowotworowego POLSKA AKADEMIA NAUK Instytut Medycyny Doświadczalnej i Klinicznej im. Mirosława Mossakowskiego Analiza efektu przeciwbólowego nowych analogów neuropeptydów w mysim modelu bólu nowotworowego Anna Leśniak Rozprawa doktorska wykonana w Zakładzie Neuropeptydów Promotor: prof. dr hab. n. med Andrzej W. Lipkowski Warszawa, 2013 http://rcin.org.pl Pragnę złożyć serdeczne podziękowania: Panu prof. dr hab. n. med. Andrzejowi Lipkowskiemu za podjęcie się roli promotora pracy oraz za opiekę merytoryczną, cenne rady i wskazówki na każdym etapie wykonywania pracy Paniom prof. dr hab. n.med Janinie Rafałowskiej oraz dr n. biol. Hannie Szymańskiej za pomoc w wykonaniu i interpretacji badań histologicznych Panom prof. Gézie Tóth oraz dr Sándorowi Benyhe za użyczenie radioligandów oraz pomoc w badaniach radioizotopowych Panu dr hab. Mariuszowi Sacharczukowi za pomoc w badaniach farmakologicznych a także Koleżankom i Kolegom z Zakładu Neuropeptydów IMDiK PAN za wsparcie i stworzenie miłej atmosfery pracy Anna Leśniak 2 http://rcin.org.pl SPIS TREŚCI: 1. WSTĘP ................................................................................................................. 9 1.1 Funkcja i definicja bólu .................................................................................... 9 1.2 Fizjologia bólu ................................................................................................ 9 1.3 Charakterystyka i funkcja receptorów opioidowych ....................................... 16 1.4 Endogenne ligandy receptorów opioidowych ................................................ 21 1.5 Mechanizmy hamowania bólu przez związki opioidowe ................................ 26 1.6 Mechanizm analgezji obwodowej .................................................................. 35 1.7 Ból nowotworowy ........................................................................................ 38 1.7.1 Klasyfikacja i etiologia bólu nowotworowego ............................................... 38 1.7.2 Farmakoterapia bólu nowotworowego ......................................................... 43 2. CELE PRACY: ....................................................................................................... 50 3. MATERIAŁY I METODY ........................................................................................ 52 3.1 Doświadczenia radioizotopowe .................................................................... 52 3.1.2 Przygotowanie homogenatu z mózgu szczura .............................................. 52 3.1.3 Kompetycyjne wiązanie radioizotopowe ...................................................... 53 3.1.4 Analiza [35S]GTPγS ......................................................................................... 54 3.2 Doświadczenia in vitro .................................................................................. 54 3.2.1 Hodowla komórek czerniaka linii B16F0 ....................................................... 54 3.2.2 Test przeżywalności komórek ........................................................................ 55 3.3 Doświadczenia in vivo ................................................................................... 56 3.3.1 Zwierzęta ....................................................................................................... 56 3.3.2 Implantacja komórek czerniaka linii B16F0 ................................................... 56 3.3.3 Preparatyka mikroskopowa ........................................................................... 57 3.3.4. Test podeszwowy oraz test cofania ogona ................................................... 58 3.3.5 Pomiar rozwoju termicznej hiperalgezji ........................................................ 59 3.3.6 Pomiar objętości kończyny ............................................................................ 59 3.3.7 Doświadczenia farmakologiczne ................................................................... 59 3.4 Związki użyte w doświadczeniach in vivo ...................................................... 60 3.5 Statystyczna analiza wyników ....................................................................... 61 3 http://rcin.org.pl 4. WYNIKI .............................................................................................................. 61 4.1 Charakterystyka morfologiczna i behawioralna mysiego modelu bólu nowotworowego .......................................................................................... 61 4.2 Farmakodynamika bifaliny i peptydów 5320 oraz 5311 w kompetycyjnych i funkcjonalnych badaniach radioizotopowych ................................................... 72 4.3 Działanie analgetyczne bifaliny i peptydów 5320 oraz 5311 w teście podeszwowym ....................................................................................... 78 4.4 Działanie analgetyczne bifaliny i peptydów 5320 oraz 5311 w teście cofania ogona ......................................................................................... 89 4.5 Porównanie udziału analgezji ośrodkowej i obwodowej bifaliny i peptydów 5320 oraz 5311..................................................................... 94 4.6 Rozwój tolerancji na bifalinę, peptyd 5320 oraz morfinę .................................... 98 5. DYSKUSJA .......................................................................................................... 102 6. WNIOSKI ........................................................................................................... 119 7. STRESZCZENIE.................................................................................................... 120 8. ABSTRACT ......................................................................................................... 123 9. LITERATURA ...................................................................................................... 128 4 http://rcin.org.pl SPIS SKRÓTÓW %MPE – % maksymalnego możliwego efektu analgetycznego [35S]GTPγS – guanozyno 5-O- [γ-35S]-trifosforan 5-HT – 5-hydroksytryptamina 5-HT2 – receptor serotoninergiczny - 2 AMPA – kwas α-amino-3-hydroksy-5-metylo-4-izoksazolo-propionowy ANOVA – analiza wariancji ASIC – kanał aktywowany protonami AUC – pole powierzchni pod krzywą B1 – receptor dla bradykininy - 1 BAM – bydlęcy peptyd rdzenia nadnerczy BBB – bariera krew-mózg BK – bradykinina CaMK– kinaza zależna od jonów wapnia i kalmoduliny cAMP – cykliczny 3',5'- adenozynomonofosforan CCK– cholecystokinina cGMP – cykliczny 3'5'-guanozynomonofosforan CGRP – peptyd związany z genem kalcytoniny COX-2 – cyklooksygenaza 2 CREB – białko wiążące się z elementem odpowiedzi na cAMP DALDA – amid [D-Arg2, Lys4] (1-4) dermorfiny 2 4 5 DAMGO – (D-Ala ,NMePhe ,Gly -ol)enkefalina DELT II – tyrosyl-3,5-3H]deltorfina II DPDPE – [D-Pen2,D-Pen5]enkefalina DSLET – D-Ser2-Leu-enkefalina-Thr6 EAA – aminokwasy pobudzające EAPC – Europejskie Stowarzyszenia Opieki Paliatywnej EDTA – kwas etylenodiaminotetraoctowy ERK 1 i 2 – kinaza zależna od sygnału zewnątrzkomórkowego 1 i 2 FBS – bydlęca surowica płodowa 5 http://rcin.org.pl GABA – kwas γ-aminomasłowy GDP – guanozyno-5'-difosforan GIRK – sprzężone z białkiem G wewnątrzprostownicze kanały potasowe GPCR – receptory sprzężone z białkiem G GTP – guanozyno-5'-trifosforan IASP– Międzynarodowe Stowarzyszenie Badania Bólu IL-1β – interleukina - 1β IL-2 – interleukina -2 IP3 – inozytolotrifosforan KAR – receptor kainianowy LC – jądro sinawe pnia mózgu LNAAT – transporter dużych obojętnych aminokwasów LOX – lipooksygenaza LT – neuron o niskim progu pobudzenia M3G – morfino-3-glukuronian M6G – morfino-6-glukuronian MAPK – kinaza białkowa aktywowana mitogenami mGluR – metabotropowy receptor glutamatergiczny NK-1 – neurokinina-1 NKA – neurokinina A NLPZ – niesterydowe leki przeciwzapalne NLX – naltrekson NLXM – metylojodek naloksonu NMDA – kwas N-metylo-D-asparaginowy NO – tlenek azotu NOS – syntaza tlenku azotu NRM – jądro wielkie szwu NS – neurony nocyceptywne NTDDS – System Celowanego Dostarczania Leku do Neuronu ORL1 – receptor opioidopodobny - 1 OUN – ośrodkowy układ nerwowy 6 http://rcin.org.pl P75 NGF – receptor dla neurotrofiny p75 PAG – substancja szara okołowodociągowa PBS – sól fizjologiczna buforowana fosforanami (pre-) PDYN – (pre-) prodynorfina (pre-) PENK – (pre-) proenkefalina PEI – polietyloimina PG – prostaglandyna PKA – kinaza białkowa A PKC – kinaza białkowa C PLA2 – fosfolipaza A2 PLC – fosfolipaza C (pre-) PNOC – (pre-) pronocyceptyna (pre-) POMC – (pre-) proopiomelanokortyna PPT – preprotachykinina PTX – toksyna krztuścowa RM ANOVA – analiza wariancji z powtarzanymi pomiarami RT-PCR – reakcja łańcuchowa polimerazy z przyrostem produktu w czasie rzeczywistym RVM – brzuszno-dogłowowa część rdzenia przedłużonego SP – substancja P TRKA – kinaza tyrozynowa A TRP – kanał jonowy aktywowany przejściowym potencjałem TRPV1 – receptor waniloidowy-1 TRPV4 – receptor waniloidowy-4 TTX – tetrodotoksyna VGCC – zależny od napięcia kanał wapniowy VPL – jądro brzuszne tylno-boczne WDR – neuron konwergencyjny WHO – Światowa Organizacja Zdrowia 7 http://rcin.org.pl CZĘŚĆ TEORETYCZNA 8 http://rcin.org.pl 1. WSTĘP 1.1 Funkcja i definicja bólu Ból jest zjawiskiem towarzyszącym człowiekowi od zarania dziejów a opisy tego zjawiska sięgają czasów starożytnego Egiptu i Babilonu. Słowo "ból" pochodzi od łacińskiego wyrazu „poena” oznaczającego karę. Ból ostry jest zjawiskiem nieodłącznie związanym z życiem człowieka, gdyż sygnalizuje zagrożenie dla integralności i homeostazy organizmu. Biologiczna, czyli ostrzegawcza funkcja bólu prowadzi do wytworzenia
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