Akut ve kronik ağrıda amigdala'ya uygulanan CDP-kolin'in analjezik etkisinin tanımlanması
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Date
2013
Authors
Özbölük, Hasret Yücel
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Publisher
Uludağ Üniversitesi
Abstract
Amigdala endojen ağrı kontrolü ile ilgili beyin bölgeleriyle bağlantısı nedeniyle hem emosyonel-affektif ağrı cevabı hem de ağrı modülasyonunda anahtar rol oynayan santral bir yapıdır. CDP-kolin, vücutta endojen olarak üretilen nükleotid yapısında bir bileşiktir ve laboratuvarımızda yapılan çalışmalarda santral yolla uygulandığında farklı ağrı modellerinde güçlü analjezik ve antihiperaljezik etki göstermiştir. Bu tez çalışmasında da deneysel ağrı modellerinde amigdalaya uygulanan CDP-kolin’in analjezik ve antihiperaljezik etkisi ve etkiye aracılık eden mekanizmalar değerlendirildi. Çalışmada Sprague-Dawley erkek sıçanlar kullanıldı. İlaçlar, amigdalanın santral nukleus bölgesine (CeA) 0.5 μl hacimde olacak şekilde uygulandı. Nöropatik ağrı, sıçanların sol siyatik sinirleri bağlanarak oluşturuldu. Akut ve nöropatik ağrı duyarlılığı mekanik pençe çekme testi ile ölçülerek değerlendirildi. CDP-kolin (1 μmol), zamana bağlı olacak şekilde akut ve nöropatik ağrı modellerinde analjezik ve antihiperaljezik etki meydana getirdi. CDP- kolin’in nöropatik ağrı modelindeki antihiperaljezik etkisi eşmolar dozda (1 μmol) uygulanan kolin ile taklit edilirken, eşmolar dozdaki (1 μmol) sitidin ile hafif ama istatistiksel olarak anlamlı antihiperaljezik etki meydana getirdi. Amigdala içine uygulanan mekamilamin (seçici olmayan nikotinik reseptör antagonisti, 3 μg), MLA (α7 nöronal nikotinik reseptör antagonisti, 10 μg), CGP-35348 (GABAB reseptör antagonisti, 3 μg), nalokson (seçici olmayan opioid reseptör antagonisti, 1 μg), metiserjid (seçici olmayan serotonin reseptör antagonisti, 5 μg) ve LY341495 (grup II metabotropik glutamat reseptör [mGLUR2/3] antagonisti; 5 μg) ön tedavileri CDP-kolin’in nöropatik ağrı modelindeki antihiperaljezik etkisini baskılarken, atropin (seçici olmayan muskarinik reseptör antagonisti, 1 μg) ön tedavisi ise etkiyi değiştirmedi. Elde edilen bulgulara göre sıçanlarda amigdalaya uygulanan CDP- kolin akut ve nöropatik ağrı modellerinde analjezik ve antihiperaljezik etki iii meydana getirmiştir. CDP-kolin’in antihiperaljezik etkisine α7 nikotinik kolinerjik reseptörler üzerinden kolinerjik mekanizmaların aktivasyonu ile birlikte amigdalada bulunan GABAB, serotonerjik, opioiderjik ve mGLUR2/3 reseptörlerinin aracılık ettiği, bununla birlikte kolinerjik muskarinik reseptörlerin rolünün olmadığı düşünülmüştür.
The amygdala is a central structure that plays a critical role in both emotional-affective pain response and modulation of pain because of its interactions with brain regions related to endogenous pain control. CDP- choline is an endogenous nucleotide which was shown to elicit potent analgesic and antihyperalgesic effects via central administration in several pain models in the studies performed in our laboratory. In this study, the analgesic and antihyperalgesic effects of CDP-choline administered intra- amygdala in experimental pain models, as well as the mechanism involved in these effects were investigated. Experiments were performed using male Sprague-Dawley rats. All drugs were administered into the central nucleus of amygdala (intra-CeA) in 0.5 μl volume. Neuropathic pain was performed by ligation of left sciatic nerve of rats. The acute and neuropathic pain sensitivities were evaluated by mechanical paw withdrawal test. CDP-choline (1 μmol), exerted analgesic and antihyperalgesic effects in a time-dependent manner in acute and neuropathic pain models. Whereas the antihyperalgesic effect of CDP-choline in neuropathic pain model was replicated by equimolar dose of (1 μmol) choline, an equimolar dose of (1 μmol) cytidine showed light but statistically significant antihyperalgesic effect. Although mecamylamine (nonspecific nicotinic receptor antagonist, 3 μg), methylicaconitine (selective α7 nicotinic receptor antagonist, 10 μg), naloxone (non-specific opioid receptor antagonist, 1 μg), CGP-35348 (GABAB receptor antagonist, 3 μg), methysergide (non-specific serotonin receptor antagonist, 5 μg) and LY341495 (metabotropic glutamate II receptor [mGLUR2/3] v antagonist, 5 μg) pretreatments administered intra-amygdala suppressed the antihyperalgesic effect of CDP choline in neuropathic pain model, atropine (nonspecific muscarinic receptor antagonist, 1 μg) pretreatment did not change the effect. These data indicate that CDP-choline administered intra-amygdala in rats exhibits analgesic and antihyperalgesic effects in acute and neuropathic pain models. Activation of cholinergic mechanisms through α7 nicotinic cholinergic receptors as well as amygdaloid GABAB, serotonin, opioid, mGLUR2/3 receptors, but not cholinergic muscarinic receptors, is likely to be involved in the antihyperalgesic effect of CDP-choline.
The amygdala is a central structure that plays a critical role in both emotional-affective pain response and modulation of pain because of its interactions with brain regions related to endogenous pain control. CDP- choline is an endogenous nucleotide which was shown to elicit potent analgesic and antihyperalgesic effects via central administration in several pain models in the studies performed in our laboratory. In this study, the analgesic and antihyperalgesic effects of CDP-choline administered intra- amygdala in experimental pain models, as well as the mechanism involved in these effects were investigated. Experiments were performed using male Sprague-Dawley rats. All drugs were administered into the central nucleus of amygdala (intra-CeA) in 0.5 μl volume. Neuropathic pain was performed by ligation of left sciatic nerve of rats. The acute and neuropathic pain sensitivities were evaluated by mechanical paw withdrawal test. CDP-choline (1 μmol), exerted analgesic and antihyperalgesic effects in a time-dependent manner in acute and neuropathic pain models. Whereas the antihyperalgesic effect of CDP-choline in neuropathic pain model was replicated by equimolar dose of (1 μmol) choline, an equimolar dose of (1 μmol) cytidine showed light but statistically significant antihyperalgesic effect. Although mecamylamine (nonspecific nicotinic receptor antagonist, 3 μg), methylicaconitine (selective α7 nicotinic receptor antagonist, 10 μg), naloxone (non-specific opioid receptor antagonist, 1 μg), CGP-35348 (GABAB receptor antagonist, 3 μg), methysergide (non-specific serotonin receptor antagonist, 5 μg) and LY341495 (metabotropic glutamate II receptor [mGLUR2/3] v antagonist, 5 μg) pretreatments administered intra-amygdala suppressed the antihyperalgesic effect of CDP choline in neuropathic pain model, atropine (nonspecific muscarinic receptor antagonist, 1 μg) pretreatment did not change the effect. These data indicate that CDP-choline administered intra-amygdala in rats exhibits analgesic and antihyperalgesic effects in acute and neuropathic pain models. Activation of cholinergic mechanisms through α7 nicotinic cholinergic receptors as well as amygdaloid GABAB, serotonin, opioid, mGLUR2/3 receptors, but not cholinergic muscarinic receptors, is likely to be involved in the antihyperalgesic effect of CDP-choline.
Description
Keywords
Amigdala, CDP-kolin, Nöropatik ağrı, Antihiperaljezik, Nikotinik reseptörler, Amygdala, CDP-choline, Neuropathic pain, Antihyperalgesic, Nicotinic receptors
Citation
Özbölük, H. Y. (2013). Akut ve kronik ağrıda amigdala'ya uygulanan CDP-kolin'in analjezik etkisinin tanımlanması. Yayınlanmamış uzmanlık tezi. Uludağ Üniversitesi Tıp Fakültesi.