Sıçanlarda oxaliplatinin neden olduğu nöropatik ağrıda CDP-kolinin etkisi ve etki mekanizması
Loading...
Files
Date
2013
Authors
Kanat, Özkan
Journal Title
Journal ISSN
Volume Title
Publisher
Uludağ Üniversitesi
Abstract
Oxaliplatin (OXA), gastrointestinal sistem kanserlerinin tedavisinde yaygın olarak kullanılan üçüncü kuĢak, platin bileĢiği bir kemoterapötik ilaçdır ve ağrılı periferik nöropati OXA’nın en önemli yan etkilerinden birisidir. CDP-kolin, vücutta endojen olarak sentezlenen bir nükleotiddir ve akut, nöropatik ve inflamatuvar ağrı modellerinde ekzojen (intraserebroventriküler [i.s.v.] veya lokal yolla) uygulanan CDP-kolin’in analjezik ve antihiperaljezik etki meydana getirdiği bilinmektedir. Bu çalıĢmada OXA’nın neden olduğu nöropatik ağrıda CDP-kolin’in antihiperaljezik etkisi ve etki mekanizmasının araĢtırılması amaçlandı. Deney hayvanı olarak sıçanlar kullanıldı ve ağrı eĢiği Randall- Selitto cihazı ile pençe çekme eĢiği olarak değerlendirildi. Sıçanlara tek doz (6 mg/kg) intraperitoneal yolla uygulanan OXA, uygulamadan bir gün sonra baĢlayan ve 14 gün süreyle devam eden mekanik hiperaljeziye neden oldu. OXA uygulamasından 48 saat sonra i.s.v. yolla uygulanan CDP-kolin (0.5, 1.0 ve 2.0 μmol), OXA’nın neden olduğu mekanik hiperaljeziyi doza ve zamana bağlı olarak azalttı. EĢmolar dozlarda (1 μmol;i.s.v.) uygulanan CDP-kolin’in hidroliz ürünü kolin ve sitidin de CDP-kolin’e benzer Ģekilde antihiperaljezik etki gösterdi. CDP-kolin’in antihiperaljezik etkisi, yüksek afiniteli nöronal kolin geri alım inhibitörü hemikolinyum-3 (1 μg; i.s.v.), selektif olmayan nikotinik kolinerjik reseptör antagonisti mekamilamin (50 μg; i.s.v.), selektif α7 nikotinik asetilkolin reseptör (nAChR) antagonisti α-bungarotoxin (2 μg; i.s.v.) ve spesifik GABAB reseptör antagonisti CGP-35348 (20 μg; i.s.v.) ön tedavileri ile önlendi. Bununla birlikte, selektif olmayan opioid reseptör antagonisti nalokson (10 μg; i.s.v.) ve selektif olmayan muskarinik reseptör antagonisti atropin (10 μg; i.s.v.) ön tedavileri, CDP-kolin’in antihiperaljezik etkisini değiĢtirmedi. Bu çalıĢmadan elde elde edilen sonuçlara göre, merkezi yolla uygulanan CDP-kolin’in OXA tedavisinin neden olduğu nöropatik hiperaljeziyi azalttığı ve CDP-kolin’in bu etkisine presinaptik kolinerjik mekanizmalarla birlikte supraspinal α7 nAChR ve GABAB reseptörlerinin aracılık ettiği ilk defa gösterildi.
Oxaliplatin (OXA) is a third-generation platinum compound that is commonly used for the treatment gastrointestinal cancer, and painful peripheral neuropathy is one of the most important side effects of OXA. CDP-choline is synthesized endogenously in the body, and it is known that exogenously administered (intracerebroventricularly [i.c.v.] or locally) CDP-choline produces analgesic and anti-hyperalgesic effects in acute, neuropathic and inflammatory pain models. In this study, we aimed to investigate the anti-hyperalgesic effect of CDP-choline and the mechanisms of its anti-hyperalgesic action in OXA-induced neuropathic pain. Rats were used in the experiment, and paw withdrawal pain threshold was assessed using the Randall-Selitto instrument. Intraperitoneal administration of a single dose (6 mg/kg) OXA to the rats caused mechanical hyperalgesia beginning on day 1 and continuing through 14 days after the injection. CDP-choline (0.5, 1.0 and 2.0 μmol), which was given i.c.v. 48 hours after OXA injection, significantly reduced OXA-induced mechanical hyperalgesia, in a dose- and time-dependent manner. Equimolar doses (1 μmol; i.c.v.) of choline and cytidine (hydrolysis products of CDP-choline) also showed significant antihiperalgesic effect. The antihyperalgesic effect of CDP-choline was blocked by the pretreatment with neuronal high affinity choline uptake inhibitor hemicholinium-3 (1 μg; i.c.v.), nonselective nicotinic receptor antagonist mecamylamine (50 μg; i.c.v.), α7 selective nicotinic acetylcholine receptor antagonist α-bungarotoxin (2 μg; i.c.v.), and gamma-amino butyric acid (GABA)-B receptor antagonist CGP-35348 (20 μg; i.c.v.). However, it was not changed by the pretreatment with nonselective opioid receptor antagonist naloxone (10 μg; icv) and nonselective muscarinic receptor antagonist atropine (10 μg; icv). The results of the present study demonstrated that for the first time centrally administered CDP-choline attenuates hyperalgesia caused by OXA treatment, and antihyperalgesic effect of CDP-choline is mediated by a presynaptic cholinergic mechanisms and activation supraspinal α7 nAChR and GABAB receptors
Oxaliplatin (OXA) is a third-generation platinum compound that is commonly used for the treatment gastrointestinal cancer, and painful peripheral neuropathy is one of the most important side effects of OXA. CDP-choline is synthesized endogenously in the body, and it is known that exogenously administered (intracerebroventricularly [i.c.v.] or locally) CDP-choline produces analgesic and anti-hyperalgesic effects in acute, neuropathic and inflammatory pain models. In this study, we aimed to investigate the anti-hyperalgesic effect of CDP-choline and the mechanisms of its anti-hyperalgesic action in OXA-induced neuropathic pain. Rats were used in the experiment, and paw withdrawal pain threshold was assessed using the Randall-Selitto instrument. Intraperitoneal administration of a single dose (6 mg/kg) OXA to the rats caused mechanical hyperalgesia beginning on day 1 and continuing through 14 days after the injection. CDP-choline (0.5, 1.0 and 2.0 μmol), which was given i.c.v. 48 hours after OXA injection, significantly reduced OXA-induced mechanical hyperalgesia, in a dose- and time-dependent manner. Equimolar doses (1 μmol; i.c.v.) of choline and cytidine (hydrolysis products of CDP-choline) also showed significant antihiperalgesic effect. The antihyperalgesic effect of CDP-choline was blocked by the pretreatment with neuronal high affinity choline uptake inhibitor hemicholinium-3 (1 μg; i.c.v.), nonselective nicotinic receptor antagonist mecamylamine (50 μg; i.c.v.), α7 selective nicotinic acetylcholine receptor antagonist α-bungarotoxin (2 μg; i.c.v.), and gamma-amino butyric acid (GABA)-B receptor antagonist CGP-35348 (20 μg; i.c.v.). However, it was not changed by the pretreatment with nonselective opioid receptor antagonist naloxone (10 μg; icv) and nonselective muscarinic receptor antagonist atropine (10 μg; icv). The results of the present study demonstrated that for the first time centrally administered CDP-choline attenuates hyperalgesia caused by OXA treatment, and antihyperalgesic effect of CDP-choline is mediated by a presynaptic cholinergic mechanisms and activation supraspinal α7 nAChR and GABAB receptors
Description
Keywords
Oxaliplatin, Nöropatik ağrı, Hiperaljezi, CDP-kolin, Neuropathic pain, Hyperalgesia, CDP-choline
Citation
Kanat, Ö. (2013). Sıçanlarda oxaliplatinin neden olduğu nöropatik ağrıda CDP-kolinin etkisi ve etki mekanizması. Yayınlanmamış doktora tezi. Uludağ Üniversitesi Sağlık Bilimleri Enstitüsü.