Farelerde morfine tolerans ve bağımlılık gelişiminde hidrojen sülfürün rolü
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Dosyalar
Tarih
2019
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Trakya Üniversitesi, Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Hidrojen sülfür ağrı oluşumu mekanizmalarında rol aldığı gösterilmiş olan endojen bir gaz mediyatördür Vücutta başlıca sistatyonin-?-sentaz ve sistatyonin-?liyaz enzimleri tarafından, L-sistein amino asidinden sentez edilir. Bu çalışmada, tolerans ve bağımlılığın gelişiminin çeşitli zamanlarında beyin ve omurilik hidrojen sülfür düzeylerindeki değişimi tespit etmeyi ve hidrojen sülfürün endojen olarak üretiminin inhibe edilmesinin tolerans ve bağımlılık oluşumu üzerine etkisinin olup olmadığını belirlemeyi amaçladık. Morfine tolerans ve bağımlılık, 12 gün boyunca günde iki kez morfin (10 mg/kg) subkutan enjeksiyonuyla oluşturuldu. Fiziksel bağımlılık 12. gün tek doz naloksonun (5 mg/kg) intraperitoneal verilmesini takiben meydana gelen yoksunluk sendromu bulgusu olan sıçrama hareketinin 20 dakika süresince sayılmasıyla belirlendi. Sistatyonin-?-liyaz inhibitörü olarak propargilglisin (30 mg/kg, i.p. 1x1) ve sistatyonin-?-sentaz inhibitörü olarak da hidroksilamin (12,5 mg/kg, i.p.1x1) kullanılmıştır. Tail flick ve hot plate testleri morfinin antinosiseptif etkisinin kaybı ve tolerans gelişimini belirlemek için kullanıldı. Kronik ve akut kullanılan propargilglisinin ve kronik kullanılan hidroksilaminin morfine tolerans gelişimini önlediği belirlendi. Tolerans gruplarında hidrojen sülfür sentaz enzim inhibitörlerinin kronik ve akut uygulamasının, beyin ve omurilik hidrojen sülfür düzeylerinde istatistiksel olarak anlamlı farklılık oluşturmadığı saptandı. Kronik ve akut propargilglisin ve hidroksilamin kullanımının morfin bağımlılığı üzerine bir etki oluşturmadığı; beyin omurilik hidrojen sülfür düzeylerinde de farklılık oluşturmadığı belirlendi. Morfin toleransını önlemede kronik ve akut kullanılan propargilglisinin ve kronik kullanılan hidroksilaminin etkili olduğu görülmüştür ancak etkinin yeri (omurilik ya da beyin düzeyi) belirlenememiştir. Tüm bu veriler doğrultusunda hidrojen sülfür sentaz enzim inhibitörleri morfin toleransının önlenmesinde ve toleransın mekanizmasının anlaşılmasında rol alabilir.
Hydrogen sulfide is an endogenous gaseous mediator that has been indicated to have a role in pain mechanisms. It is mainly synthesized from the amino acid Lcysteine by cystathionine-?-synthase and cystathionine-?-lyase enzymes in the body. In this study, we aimed to detect brain and spinal cord hydrogen sulfide levels during different terms of tolerance and dependence to morphine and to determine the effects of inhibition of endogenous hydrogen sulfide production on the development of tolerance and dependence. Morphine tolerance and dependence was developed with subcutaneous injection of morphine (10 mg/kg) twice daily for 12 days. Physical dependence was determined by counting the jumps for 20 minutes which is a withdrawal symptom occuring after a single dose of naloxone (5 mg/kg) administered intraperitoneally. Propargylglycine (30 mg/kg, i.p. 1x1) was used as a cystathionine?-lyase inhibitor and hydroxylamine (12,5 mg/kg, i.p.1x1) was used as a cystathionine-?-synthase inhibitor. The tail flick and hot plate tests were used to determine the loss of antinociceptive effects of morphine and development of tolerance. It was found that chronic and acute use of propargylglycine and chronic use of hydroxylamine prevent the development of tolerance to morphine. It was determined that chronic and acute administration of hydrogen sulfide synthase inhibitors does not create a statistically significant difference in hydrogen sulfide levels in brain and spinal cord in tolerance groups. It was also found that in chronic and acute administrations of propargylglycine and hydroxylamine had no effect on morphine dependence; no difference was found in hydrogen sulfide levels in brain and spinal cord. Chronic and acute administrations of propargylglycine and chronic administration of hydroxylamine were found to be effective in preventing morphine tolerance, however its site of action (brain or spinal cord levels) could not be determined. It has been concluded according to the data that hydrogen sulfide synthase inhibitors may take role in preventing morphine tolerance and understanding the mechanism of tolerance.
Hydrogen sulfide is an endogenous gaseous mediator that has been indicated to have a role in pain mechanisms. It is mainly synthesized from the amino acid Lcysteine by cystathionine-?-synthase and cystathionine-?-lyase enzymes in the body. In this study, we aimed to detect brain and spinal cord hydrogen sulfide levels during different terms of tolerance and dependence to morphine and to determine the effects of inhibition of endogenous hydrogen sulfide production on the development of tolerance and dependence. Morphine tolerance and dependence was developed with subcutaneous injection of morphine (10 mg/kg) twice daily for 12 days. Physical dependence was determined by counting the jumps for 20 minutes which is a withdrawal symptom occuring after a single dose of naloxone (5 mg/kg) administered intraperitoneally. Propargylglycine (30 mg/kg, i.p. 1x1) was used as a cystathionine?-lyase inhibitor and hydroxylamine (12,5 mg/kg, i.p.1x1) was used as a cystathionine-?-synthase inhibitor. The tail flick and hot plate tests were used to determine the loss of antinociceptive effects of morphine and development of tolerance. It was found that chronic and acute use of propargylglycine and chronic use of hydroxylamine prevent the development of tolerance to morphine. It was determined that chronic and acute administration of hydrogen sulfide synthase inhibitors does not create a statistically significant difference in hydrogen sulfide levels in brain and spinal cord in tolerance groups. It was also found that in chronic and acute administrations of propargylglycine and hydroxylamine had no effect on morphine dependence; no difference was found in hydrogen sulfide levels in brain and spinal cord. Chronic and acute administrations of propargylglycine and chronic administration of hydroxylamine were found to be effective in preventing morphine tolerance, however its site of action (brain or spinal cord levels) could not be determined. It has been concluded according to the data that hydrogen sulfide synthase inhibitors may take role in preventing morphine tolerance and understanding the mechanism of tolerance.
Açıklama
Anahtar Kelimeler
Morfin, Tolerans, Bağımlılık, Hidrojen Sülfür, Morphine, Tolerance, Dependence, Hydrogen Sulfide
