Intracerebroventricular Application of Dexmedetomidine Produces Antinociception and Does not Cause Neurotoxicity in Rats

Abstract

Background: Alpha2 agonists contribute to pain control at the level of the medulla spinalis. Alpha2 agonists are generally added to local anaesthetics to prolong spinal or epidural anaesthesia time. Aims: In the present study, we aimed to evaluate the antinociceptive and neurotoxic effects of dexmedetomidine given intracerebroventricularly for 5 days. Study Design: Animal experimentation. Methods: After intraventricular cannulation, rats (n=32) were divided into two groups (n=16 each). Rats in the dexmedetomidine group (Group D, n=16) received 3 µg (0.03 mL) dexmedetomidine and the control group (Group C, n=16) received 0.03 mL physiological serum through an intracerebroventricular catheter once a day, for 5 days. Antinociceptive, sedative, and motor effects were evaluated before the injection and for 90 min after injection. The tail-flick and hot plate tests were used to assess thermal nociceptive threshold. For histopathological evaluation, half of the rats in both groups were sacrificed on the 6th day and the remaining rats were sacrificed on the 21st day. Then the perfusion fixation method was applied. The first tissue section was obtained from the cervical spinal cord 1 cm distal to the proximal end of the spinal cord. The second sample was retrieved from the region 1 cm distal from the thoracic 13-lumbar 1 vertebra. On morphological evaluation, nonspecific changes like edema and gliosis, signs of neuronal degeneration demonstrating a severe reaction, and density of inflammatory cells were examined. Results: In dexmedetomidine-administered rats, on the first day reaction times at 5, 10, and 20 min and on the other days, reaction times at 5, 10, 20, and 30 min in hot plate tests were significantly longer compared with baseline values (p<0.05). In dexmedetomidine-administered rats, on the 1st, 4th, and 5th days reaction times at 5, 10, 20, 30, and 40 min and on the 2nd and 3rd days reaction times at 5, 10, 20, and 30 min in tail-flick tests were significantly longer compared with baseline values (p<0.05). First-degree sedation lasting for 60 min and first-degree motor block lasting for 30–40 min were observed in the dexmedetomidine group. Similar rates of nonspecific changes such as edema and gliosis were seen in both groups. Signs of severe reactions such as neuronal degeneration and diffuse inflammatory cell infiltration were not encountered in any group. There was no significant difference between groups according to morphological findings of the spinal cord on the 6th and 21st days (p>0.05). Conclusion: We observed that intracerebroventricular administration of 3 μg dexmedetomidine produced antinociception and did not cause neurotoxicity. Turkish Başlık:: İntraserebroventriküler Deksmedetomidin Uygulaması Ratlarda Antinosisepsiyon Sağlar ve Nörotoksisiteye Neden Olmaz Anahtar Kelimeler:Deksmedetomidin, antinosisepsiyon, nörotoksisite Arkaplan: Alfa2 agonistler medulla spinalis seviyesinde ağrı kontrolüne katkıda bulunurlar. Spinal veya epidural anestezi süresini uzatmak amacıyla alfa2 agonistler sıklıkla lokal anestezik ajanlara ilave edilmektedir. Amaç: Biz bu çalışmada; deksmedetomidini intraserebroventriküler yoldan beş gün boyunca uygulayarak antinosiseptif ve nörotoksik etkisini araştırmayı amaçladık. Çalışma Tasarımı: Paralel deneysel çalışma. Yöntemler: İntraventriküler kanülasyon sonrası ratlar (n=32) iki gruba ayrıldı. Deksmedetomidin grubundaki ratlara (n=16) 3 μg (0.03 mL) dekmedetomidin ve kontrol grubundakilere (n=16) 0.03 mL serum fizyolojik intraventriküler kateter yoluyla günde bir kez olacak şekilde 5 gün boyunca uygulandı. Antinosiseptf, sedatif ve motor etkiler enjeksiyon öncesi ve 90 dakika boyunca değerlendirildi. Analjezik etkinliği değerlendirmek için kuyruk batırma ve sıcak zemin testleri kullanıldı. Histopatolojik değerlendirme için her iki gruptaki ratların yarısı 6. günde, kalan ratlar 21. günde sakrifiye edildi ve perfüzyon fiksasyon uygulandı. Doku kesitlerinden birincisi spinal kordun başlangıcının 1 cm distalindeki servikal spinal korddan alındı. İkincisi ise torakal 13-lomber 1 seviyesinin 1 cm distalindeki lomber bölgeden alındı. Morfolojik değerlendirmede ödem, gliozis gibi nonspesifik değişiklikler ve şiddetli reaksiyonu gösteren nöronal dejenerasyon bulguları ve inflamatuvar hücre yoğunluğu değerlendirildi. Bulgular: Deksmedetomidin uygulanan ratlarda, sıcak zemin testinde ilk gün 5., 10., 20. dakikalardaki ve diğer günlerde 5., 10., 20., 30. dakikalardaki reaksiyon zamanları bazal değerler ile karşılaştırıldığında anlamlı olarak uzun bulundu (p<0.05). Deksmedetomidin uygulanan ratlarda, kuyruk batırma testinde 1.,4., ve 5. günlerde 5., 10., 20., 30., 40. dakikalardaki ve 2., ve 3. günlerde 5., 10., 20., 30. dakikalardaki reaksiyon zamanları bazal değerler ile karşılaştırıldığında anlamlı olarak uzun bulundu (p<0.05). Dekmedetomidin grubunda 60 dakika devam eden birinci derece sedasyon ve 30-40 dakika devam eden birinci derece motor blok gözlemledik. Her iki grupta da ödem ve gliozis gibi nonspesifik değişiklikler benzer oranda görüldü. Nöronal dejenerasyon ve inflamatuvar hücre yoğunluğunu içeren şiddetli reaksiyon bulgularına her iki grupta da rastlanmadı. Spinal kordun morfolojik incelemesinde 6. ve 21. günlerdeki değerlendirmede de gruplar arasında histopatolojik anlamlı fark bulunamadı (p>0.05). Sonuç: İntraserebroventriküler yoldan uygulanan 3 μg deksmedetomidin antinosiseptif etkinlik gösterir ve nörotoksisiteye neden olmaz.

Keywords

• Dexmedetomidine, analgesia, neurotoxicity

Intracerebroventricular Application of Dexmedetomidine Produces Antinociception and Does not Cause Neurotoxicity in Rats

Öz

Kaynakça

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