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

References

1. Jones SL, Gebhart GF. Characterization of coeruleospinal inhibition of the nociceptive tail-flick reflex in the rat: mediation by spinal alpha 2-adrenoceptors. Brain Res 1986;364:315-30. [CrossRef]
2. D’Angelo R. Should we administer epidural or spinal clonidine during labor? Reg Anesth Pain Med 2000;25:3-4. [CrossRef]
3. Mercier FJ, Boulay G, Ber Ayed M, Benhamou D. Combined spinal and epidural analgesia for labor. Prolongation by the addition of a minidose of clonidine to sufentanil. An initial study. Ann Fr Anesth Reanim 1996;15:263-5. [CrossRef]
4. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia 1999;54:146-165. [CrossRef]
5. Lakhlani PP, MacMillan LB, Guo TZ. Substitution of a mutant alpha2 adrenergic receptor via ‘’hit and run’’ gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc Natl Acad Sci 1997;94:9950-5. [CrossRef]
6. Yaksh TL. Pharmacology of spinal noradrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav 1985;22:845-58. [CrossRef]
7. Stevens CW, Brenner GM. Spinal administration of adrenergic agents produces analgesia in amphibians. Eur J Pharmacol 1996;316:205-10. [CrossRef]
8. Loo CC, Dahlgren G, Irestedt L. Neurological complications in obstetric regional anaesthesia. Int J Obstet Anesth 2000;9:991 [CrossRef]

9. Horlocker TT, Wedel DJ. Neurologic complications of spinal and epidural anesthesia. Reg Anesth Pain Med 2000;25:83-98. [CrossRef]
10. Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates, 4th edition. San Diego, Academic Press, 1998, pp 19-66.
11. Eddy Nb, Leimbach D. Synthetic Analgesics. II. Dithienylbutenyl and Dithienylbutylamines. J Pharmacol Exp Ther 1953;107:385-93. D’Amour FE, Smith DL. A method for determining loss of pain sensation. J Pharmacol Exp Ther 1941;72:74-79.
12. Archer DP, Lamberty Y, Wang B, Davis MJ, Samanani N, Roth SH. Levetiracetam reduces anesthetic-induced hyperalgesia in rats. Anesth Analg 2007;104:180-5. [CrossRef]
13. Yamamoto T, Nozaki-Taguchi N, Chiba T. Analgesic effect of intrathecally administered orexin-A in the rat formalin test and in the rat hot plate test. Br J Pharmacol 2002;137:170-6. [CrossRef] Koizumi Y, Matsumoto M, Yamashita A, Tsuruta S, Ohtake T, Sakabe T. The effects of an AMPA receptor antagonist on the neurotoxicity of tetracaine intrathecally administered in rabbits. Anesth Analg 2006;102:930-6. [CrossRef]
14. Maze M, Tranquilli W. Alpha-2 adrenoceptor agonists: Defining the role in clinical anesthesia. Anesthesiology 1991;74:581-605. [CrossRef]
15. Eisenach JC, De Kock M, Klimscha W. Alpha2 adrenergic agonists for regional anesthesia: a clinical review of clonidine (19841995). Anesthesiology 1996;85:655-74. [CrossRef]
16. Fisher B, Zornow MH, Yaksh TL, Peterson BM. Antinociceptive properties of intrathecal dexmedetomidine in rats. Eur J Pharmacol 1991;192:221-5. [CrossRef]
17. Joo G, Horvath G, Klimscha W, Kekesi G, Dobos I, Szikszay M, et al. The effects of ketamine and its enantiomers on the morphine or dexmedetomidine-induced antinociception after intrathecal administration in rats. Anesthesiology 2000;93:231-41. [CrossRef]
18. Kalso EA, Pöyhia R, Rosenberg PH. Spinal antinociception by dexmedetomidine, a highyl selective α2-adrenergic agonist. Pharmacol Toxicol 1991;68:140-3. [CrossRef]
19. Kanazi GE, Aouad MT, Jabbour-Khoury SI, Al Jazzar MD, Alameddine MM, Al-Yaman R, et al. Effect of low dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block. Acta Anaesthesiol Scand 2006;50:222-7. [CrossRef]
20. Al-Mustafa MM, Abu-Halaweh SA, Aloweidi AS, Murshidi MM, Ammari BA, Awwad ZM, et al. Effect of dexmedetomidine added to spinal bupivacaine for urological procedures. Saudi Med J 2009;30:365-70.
21. Mohamed AA, Fares KM, Mohamed SA. Efficacy of intrathecally administered dexmedetomidine versus dexmedetomidine with fentanyl in patients undergoing major abdominal cancer surgery. Pain Physician 2012;15:339-48.
22. Xiang Q, Huang DY, Zhao YL, Wang GH, Liu YX, Zhong L, et al. Caudal dexmedetomidine combined with bupivacaine inhibit the response to hernia sac traction in children undergoing inguinal hernia repair. Br J Anaesth 2013;110:420-4. [CrossRef]
23. Espejo EF, Mir D. Structure of the rat’s behaviour in the hot plate test. Behav Brain Res 1993;56:171-6. [CrossRef]
24. Talke PO, Caldwell JE, Richardson CA, Kirkegaard-Nielsen H, Stafford M. The effects of dexmedetomidine on neuromuscular blockade in human volunteers. Anesth Analg 1999;88:633-9. [CrossRef]
25. Venn RM, Karol MD, Grounds RM. Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive car. Br J Anaesth 2002;88:669-75. [CrossRef]
26. Buerkle H, Yaksh TL. Pharmacological evidence for different alpha 2-adrenergic receptor sites mediating analgesia and sedation in the rat. Br J Anaesth 1998;81:208-15. [CrossRef]
27. Gordh T Jr, Post C, Olsson Y. Evaluation of the toxicity of subarachnoid clonidine, guanfacine and substance p-antagonist on rat spinal cord and nerve roots:Light and electron microscopic observations after chronic intrathecal administration. Anesth Analg 1986;65:1303-11. [CrossRef]
28. Gordh TE, Ekman S, Lagerstedt AS. Evaluation of possible spinal neurotoxicity of clonidine. Ups J Med Sci 1984;89:266-73. [CrossRef]
29. Konakci S, Adanir T, Yilmaz G, Rezanko T. The efficacy and neurotoxicity of dexmedetomidine administered via the epidural route. Eur J Anaesthesiol 2008;25:403-9. [CrossRef]
30. Tachibana K, Hashimoto T, Kato R, Uchida Y, Ito R, Takita K, et al. Neonatal administration with dexmedetomidine does not impair the rat hippocampal synaptic plasticity later in adulthood. Paediatr Anaesth 2012;22:713-9. [CrossRef]
31. Gul S, Hanci V, Bahadir B, Acikgoz S, Bektas S, Ankarali H, et al.The effectiveness of dexmedetomidine in experimental spinal cord injury compared to methylprednisolone in rats. J Clin Neurosci 2010;17:490-4. [CrossRef]
32. Zhu YM, Wang CC, Chen L, Qian LB, Ma LL, Yu J, et al. Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focalcerebral ischemia/reperfusion injury in rats. Brain Res 2013;1494:1-8. [CrossRef]
33. Brummett CM, Norat MA, Palmisano JM, Lydic R. Perineural administration of dexmedetomidine in combination with bupivacaine enhances sensory and motor blockade in sciatic nerve block without inducing neurotoxicity in rat. Anesthesiology 2008;109:502-11. [CrossRef]