Davut Sinan KAPLAN, Levent ŞAHİN, Tuncer DEMİR, Hasan ŞİMŞEK, Mehrican ŞAHİN, Beyhan CENGİZ, Nurgül DOLU

The effects of bupivacaine combined with different adjuvants on block onset and duration and on ion channel expressions (SCN9A, TRPM) in sciatic nerve block in rats

Background/aim: The objective of this experimental study was to examine the effects of epinephrine, dexmedetomidine, and clonidine added as adjuvants to bupivacaine on block onset and effect times, as well as the effects on the Na+ and Ca+2 channel gene expressions, which may indicate cell damage in the sciatic nerve cell membrane. Materials and methods: Rats were divided into five groups: Group S (sham), saline solution; Group B, bupivacaine; Group BD, bupivacaine + dexmedetomidine; Group BC, bupivacaine + clonidine; and Group BE, bupivacaine + epinephrine. For each group, 0.2 mL of local anesthetic was injected into the sciatic nerve bifurcation point of the right leg. Sensory (proprioceptive and nociceptive block) and motor block onset and ending times were recorded. Results: The shortest onset time for the examined sciatic block was observed in the BC group, whereas the longest sensory and motor block times were observed in the BD group. The present data suggest suppressed TRPM7 and increased TRPM2 in the groups other than the BE group. Conclusion: Clonidine is more suitable for fast onset of peripheral nerve blocks, whereas the addition of dexmedetomidine is better in terms of duration. Because the SCN9A and TRPM2,4,7 expression ratios of the BE group showed the least amount of change, this group had the best cellular integrity.

PDF

___

1. Cuvillon P NE, Ripart J, Boyer JC, Dehour L, Mahamat A, Lhermite J, Boisson C, Vialles N, Lefrant JY, de La Coussaye JE. Comparison of the pharmacodynamics and pharmacokinetics of bupivacaine, ropivacaine (with epinephrine) and their equal volume mixtures with lidocaine used for femoral and sciatic nerve blocks. Anesth Analg 2009; 108: 641-649.
2. Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 2000; 1: 11-21.
3. Harteneck C, Plant TD, Schultz G. From worm to man: three subfamilies of TRP channels. Trends Neurosci 2000; 23: 159- 166.
4. Montell C. Physiology, phylogeny, and functions of the TRP superfamily of cation channels. Sci STKE 2001; 2001: re1.
5. Montell C, Birnbaumer L, Flockerzi V. The TRP channels, a remarkably functional family. Cell 2002; 108: 595-598.
6. Alexander SP, Mathie A, Peters JA. Guide to receptors and channels, 1st edition. Br J Pharmacol 2004; 141 Suppl 1: S1- 126.
7. RM. T. Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension. Am J Physiol 2008; 294: H1103-H1118.
8. Kraft R HC. The mammalian melastatin-related transient receptor potential cation channels: an overview. Pflugers Arch 2005; 451: 204-211.
9. Kunert-Keil C, Bispring F, Kruger J, Brinkmeier H. Tissuespecific expression of TRP channel genes in the mouse and its variation in three different mouse strains. BMC Genomics 2006; 7: 159-163.
10. Montell C. An exciting release on TRPM7. Neuron 2006; 52: 395-397.
11. Vennekens R VT, Bindels RJ, Droogmans G, Nilius B. Current understanding of mammalian TRP homologues. Cell Calcium 2002; 31: 253-264.
12. Hara Y WM, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J, Shimizu N et al. LTRPC2 Ca2+ permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell Biochem 2002; 9: 163-173.
13. Perraud C JA, Inabe CO, Smith K, Penner MK, Kurosaki R, Fleig Scharenberg T. Regulation of vertebrate cellular Mg+2 homeostasis by TRPM7. Cell 2003; 114: 191-200.
14. Perraud AL KH, Schmitz C. Novel aspects of signaling and ion homeostasis regulation in immunocytes. The TRPM ion channels and their potential role in modulating the immune response. Mol Immunol 2004; 41: 657-673.
15. Earley S, Waldron BJ, Brayden JE. Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res 2004; 95: 922-929.
16. Montell C. Mg2+ homeostasis: the Mg2+nificent TRPM chanzymes. Curr Biol 2003; 13: R799-801.
17. Schmitz C, Perraud AL, Johnson CO, Inabe K, Smith MK, Penner R, Kurosaki T, Fleig A, Scharenberg AM. Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell 2003; 114: 191-200.
18. Estebe JP MR. Amitriptyline neurotoxicity: dose-related pathology after topical application to rat sciatic nerve. Anesthesiology 2004; 100: 1519-1525.
19. Thalhammer JG, Vladimirova M, Bershadsky B, Strichartz GR. Neurologic evaluation of the rat during sciatic nerve block with lidocaine. Anesthesiology 1995; 82: 1013-1025.
20. Estebe JP, Myers RR. Amitriptyline neurotoxicity: doserelated pathology after topical application to rat sciatic nerve. Anesthesiology 2004; 100: 1519-1025.
21. 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: 502-511.
22. Brummett CM, Padda AK, Amodeo FS, Welch KB, Lydic R. Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat. Anesthesiology 2009; 111: 1111-1119.
23. Li Z, Tian M, Zhang CY, Li AZ, Huang AJ, Shi CX, Xin DQ, Qi J, Li KZ. A randomised controlled trial to evaluate the effectiveness of intrathecal bupivacaine combined with different adjuvants (fentanyl, clonidine and dexmedetomidine) in caesarean section. Drug Research 2015; 65: 581-586.
24. Shahi V, Verma AK, Agarwal A, Singh CS. A comparative study of magnesium sulfate vs dexmedetomidine as an adjunct to epidural bupivacaine. J Anaesthesiol Clin Pharmacol 2014; 30: 538-542.
25. Kanazi GE, Aouad MT, Jabbour-Khoury SI, Al Jazzar MD, Alameddine MM, Al-Yaman R, Bulbul M, Baraka AS. Effect of low-dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block. Acta Anaesth Scand 2006; 50: 222- 227.
26. Hutschala D, Mascher H, Schmetterer L, Klimscha W, Fleck T, Eichler HG, Tschernko EM. Clonidine added to bupivacaine enhances and prolongs analgesia after brachial plexus block via a local mechanism in healthy volunteers. Eur J Anaesthesiol 2004; 21: 198-204.
27. Iohom G, Machmachi A, Diarra DP, Khatouf M, Boileau S, Dap F, Boini S, Mertes PM, Bouaziz H. The effects of clonidine added to mepivacaine for paronychia surgery under axillary brachial plexus block. Anesth Analg 2005; 100: 1179-1183.
28. Iskandar H, Benard A, Ruel-Raymond J, Cochard G, Manaud B. The analgesic effect of interscalene block using clonidine as an analgesic for shoulder arthroscopy. Anesth Analg 2003; 96: 260-262.
29. Butterworth JFt, Strichartz GR. The alpha 2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg 1993; 76: 295-301.
30. Mahendru V, Tewari A, Katyal S, Grewal A, Singh MR, Katyal R. A comparison of intrathecal dexmedetomidine, clonidine, and fentanyl as adjuvants to hyperbaric bupivacaine for lower limb surgery: a double blind controlled study. J Anaesthesiol Clin Pharmacol 2013; 29: 496-502.
31. Solanki SL, Bharti N, Batra YK, Jain A, Kumar P, Nikhar SA. The analgesic effect of intrathecal dexmedetomidine or clonidine, with bupivacaine, in trauma patients undergoing lower limb surgery: a randomised, double-blind study. Anaesthesia and Intensive Care 2013; 41: 51-56.
32. Kroin JS, Buvanendran A, Beck DR, Topic JE, Watts DE, Tuman KJ. Clonidine prolongation of lidocaine analgesia after sciatic nerve block in rats is mediated via the hyperpolarizationactivated cation current, not by alpha-adrenoreceptors. Anesthesiology 2004; 101: 488-494.
33. Virtanen R, Savola JM, Saano V, Nyman L. Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2-adrenoceptor agonist. Eur J Pharmacol 1988; 150: 9-14.
34. Yung E, Lahoti T, Jafari S, Weinberg JD, Schianodicola JJ, Yarmush JM, Ray SD. Bicarbonate plus epinephrine shortens the onset and prolongs the duration of sciatic block using chloroprocaine followed by bupivacaine in Sprague-Dawley rats. Reg Anesth Pain Med 2009; 34: 196-200.
35. Sinnott CJ, Cogswell IL, Johnson A, Strichartz GR. On the mechanism by which epinephrine potentiates lidocaines peripheral nerve block. Anesthesiology 2003; 98: 181-188.
36. Selander D, Mansson LG, Karlsson L, Svanvik J. Adrenergic vasoconstriction in peripheral nerves of the rabbit. Anesthesiology 1985; 62: 6-10.
37. Fink BR, Aasheim GM, Levy BA. Neural pharmacokinetics of epinephrine. Anesthesiology. 1978; 48: 263-266.
38. Partridge BL. The effects of local anesthetics and epinephrine on rat sciatic nerve blood flow. Anesthesiology 1991; 75: 243- 250.
39. Selander D, Brattsand R, Lundborg G, Nordborg C, Olsson Y. Local anesthetics: importance of mode of application, concentration and adrenaline for the appearance of nerve lesions. An experimental study of axonal degeneration and barrier damage after intrafascicular injection or topical application of bupivacaine (Marcain). Acta Anaesthesiol Scand 1979; 23: 127-136.
40. Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR. The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 2006; 7: S1-29.
41. Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, Drenth JP, Dai F, Wheeler J, Sanders F et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci USA 2010; 107: 5148-5153.
42. Sun L, Yau HY, Wong WY, Li RA, Huang Y, Yao X. Role of TRPM2 in H2 O2 -induced cell apoptosis in endothelial cells. PLoS One 2012; 7: e43186.
43. Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M. A key role for TRPM7 channels in anoxic neuronal death. Cell 2003; 115: 863-877.
44. Simard JM, Woo SK, Gerzanich V. Transient receptor potential melastatin 4 and cell death. Pflugers Arch 2012 464: 573-582.
45. Gerzanich V, Woo SK, Vennekens R, Tsymbalyuk O, Ivanova S, Ivanov A, Geng Z, Chen Z, Nilius B, Flockerzi V et al. De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat Med 2009; 15: 185-191.