Introduction: Tiletamine-xylazine-tramadol (XFM) has few side effects and can provide good sedation and analgesia. Adenosine 5’-monophosphate-activated protein kinase (AMPK) can attenuate trigeminal neuralgia. The study aimed to investigate the effects of XFM and its specific antagonist on AMPK in different regions of the brain. Material and Methods: A model of XFM in the rat was established. A total of 72 Sprague Dawley (SD) rats were randomly divided into three equally sized groups: XFM anaesthesia (M group), antagonist (W group), and XFM with antagonist interactive groups (MW group). Eighteen SD rats were in the control group and were injected intraperitoneally with saline (C group). The rats were sacrificed and the cerebral cortex, cerebellum, hippocampus, thalamus, and brain stem were immediately separated, in order to detect AMPKα mRNA expression by quantitative PCR. Results: XFM was able to increase the mRNA expression of AMPKα1 and AMPKα2 in all brain regions, and the antagonist caused the opposite effect, although the effects of XFM could not be completely reversed in some areas. Conclusion: XFM can influence the expression of AMPK in the central nervous system of the rat, which can provide a reference for the future development of anaesthetics for animals.
1. Belinda J.H., Halla M.C., Jane R.H., Graham A.J.: Flumazenilindependent positive modulation of γ-aminobutyric acid action by 6-methylflavone at human recombinant α1β 2γ2L, and α1β2 GABAA receptors. Eur J Pharmacol 2004, 491, 1–8.
2. Culmsee C., Monnig J., Kemp B.E., Mattson M.P.: AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Molec Neurosci 2001, 17, 45–58.
4. Craps J., Joris V., De J.B., Sonveaux P., Horman S., Lengelé B., Bertrand L., Many M.C., Colin I.M., Gérard A.C.: Involvement of mTOR and regulation by AMPK in early iodine deficiency-induced thyroid microvascular activation. Endocrinology 2016, 157, 2545–2559.
5. Dyck J.R., Kudo N., Barr A.J., Davies S.P., Hardie D.G., Lopaschuk G.D.: Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5’-AMP activated protein kinase. Eur J Biochem 1999, 262, 184–190.
6. Dong D., Cai G., Ning Y., Wang J.C., Lv Y., Hong Q., Cui S.Y., Fu B., Guo Y.N., Chen X.M.: Alleviation of senescence and epithelial-mesenchymal transition in aging kidney by short-term caloric restriction and caloric restriction mimetics via modulation of AMPK/mTOR signaling. Oncotarget 2017, 8, 16109–16121.
7. Fan H.G., Wang H.B., Hu K.: Dynamic effect of the compound anesthetic for miniature pigs on cAMP signal transduction system in different brain regions of SD rats. Chinese Vet Sci 2010, 40, 421–428.
8. Joungmok K., Mondira K., Benoit V., Kun-Liang G.: AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology 2011, 13, 132-141.
9. Haapalinna A., Sirviö J., Macdonald E., Virtanen R., Heinonen E.: The effects of a specific alpha(2)-adrenoceptor antagonist, atipamezole, on cognitive performance and brain neurochemistry in aged Fisher 344 rats. Eur J Pharmacol 2000, 387, 141–150.
10. Kasajima A., Pavel M., Darb-Esfahani S., Davies S.P., Hardie D.G., Lopaschuk G.D.: mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2011, 18, 181–192.
11. Kolesnikova T.O., Khatsko S.L., Shevyrin V.A., Morzherin Y.Y., Kalueff A.V.: Effects of a non-competitive N-methyl-daspartate (NMDA) antagonist, tiletamine, in adult zebrafish. Neurotoxicol Teratol 2016, 59, 62–67.
12. Kim E., Park M., Jeong J., Kim H., Lee S.K., Lee E., Oh B.H., Namkoong K.: Cholinesterase inhibitor donepezil increases mitochondrial biogenesis through AMP-activated protein kinase in the hippocampus. Neuropsychobiology 2016, 73, 81–91.
13. Girvan C.B., Dundee J.W.: Alterations in response to somatic pain associated with anaesthesia xxlll: further study of naloxone. Brit J Anaesth 1976, 48, 463–468.
14. Lu D.Z., Fan H.G., Wang H.B., Hu K., Zhang J.T., Yu S.M.: Effect of the addition of tramadol to a combination of tiletaminezolazepam and xylazine for anaesthesia of miniature pigs. Vet Rec 2010, 167, 489–492.
15. Lu D.Z.: Study on the wake up mechanism of the anesthetic agent for miniature swine. Harbin, China: Northeast Agricult Univer 2011, S858.28.
16. Li L., Dong J., Lu D., Duarte Q.L., Sheng J., Fan H.G.: Effects of iletamine-zolazepam-xylazine-tramadol combination on biochemical and haematological parameters in cats. Bull Vet Inst Pulawy 2012, 56, 369–372.
17. Livak K.J., Schmittgen T.D.: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods-A Companion To Methods in Enzymology 2001, 25, 402-408.
18. Madhusoodanan K.S., Murad F.: NO-cGMP signaling and regenerative medicine involving stem cells. Neurochem Res 2007, 32, 681–694.
19. Nakayama T., Hashimoto T., Nagai Y.: Involvement of glutamate and gamma-aminobutyric acid (GABA)-ergic systems in thyrotropin-releasing hormone-induced rat cerebellar cGMP formation. Eur J Pharmacol 1996, 316, 157–164.
20. Organization W.H.: WHO Expert Committee on Drug Dependence. Thirty-sixth report, World Health Organization; New York, Columbia University Press, International Documents Service, 2015, 998, 1–34.
21. Price T.J., Dussor G.: AMPK: An emerging target for modification of injury-induced pain plasticity. Neurosci Letters 2013, 557, 9–18.
22. Perouansky M.: Coagulation, flocculation, and denaturation: a century of research into protoplasmic theories of anesthesia. Anesth Analg 2014, 119, 311–320.
23. Radbruch L., Grond S., Lehmann K.A.: A risk-benefit assessment of tramadol in the management of pain. Drug Saf 1996, 15, 8–29.
24. Sleeman J., Stevens R., Ramsay E.: Field immobilization of muskrats (Ondatra zibethicus) for minor surgical procedures. J Wildl Dis 1997, 33, 165–168.
25. Seo J.P., Son W.G., Gang S., Lee I.: Sedative and analgesic effects of intravenous xylazine and tramadol on horses. J Vet Sci 2011, 12, 281–286.
26. Sheng J.: Effects of miniature swine combined anesthetics and its antagonist on PI3K/Akt/mTOR signaling pathway in different brain regions of rats. Harbin, China: Northeast Agricult Univer 2015, S857.124.
27. Springer A., Razafimanantsoa L., Fichtel C., Kappeler P.M.: Comparison of three short-term immobilization regimes in wild verreaux’s sifacas (Propithecus verreauxi) ketamine-xylazine, ketamine-xylazine-athropine, and tiletamine-zolozepam. J Zoo Wildlife Med 2015, 46, 482–490.
28. Shi X.X., Yin B.S., Peng Y., Chen H., Li X., Su L.X., Fan H.G., Wang H.B.: Xylazine activates adenosine monophosphateactivated protein kinase pathway in the central nervous system of rats. Plos One 2016, 11, e0153169.
29. Vulliemoz Y., Whittington R.A., Virag L.: The nitric oxidecGMP system of the locus coeruleus and the hypnotic action of alpha-2 adrenergic agonists. Brain Res 1999. 849, 169–174.
30. Vacher C.M., Hardin-Pouzet H., Steinbusch H.W., Morzherin Y.Y., Kalueff A.V.: The effects of nitric oxide on magnocellular neurons could involve multiple indirect cyclic GMP-dependent pathways. Eur J Neurosci 2003, 17, 455–466.