Biomolecules & Therapeutics

  • 제31권2호
  • /
  • Pages.168-175
  • /
  • 2023
  • /
  • 1976-9148(pISSN)
  • /
  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Nav1.7 and Nav1.5

  • Chan-Su, Bok (BK21-4th and Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea) ;
  • Ryeong-Eun, Kim (BK21-4th and Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea) ;
  • Yong-Yeon, Cho (BK21-4th and Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea) ;
  • Jin-Sung, Choi (BK21-4th and Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea)
  • 투고 : 2023.01.06
  • 심사 : 2023.01.17
  • 발행 : 2023.03.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Tramadol is an opioid analog used to treat chronic and acute pain. Intradermal injections of tramadol at hundreds of millimoles have been shown to produce a local anesthetic effect. We used the whole-cell patch-clamp technique in this study to investigate whether tramadol blocks the sodium current in HEK293 cells, which stably express the pain threshold sodium channel Nav1.7 or the cardiac sodium channel Nav1.5. The half-maximal inhibitory concentration of tramadol was 0.73 mM for Nav1.7 and 0.43 mM for Nav1.5 at a holding potential of -100 mV. The blocking effects of tramadol were completely reversible. Tramadol shifted the steady-state inactivation curves of Nav1.7 and Nav1.5 toward hyperpolarization. Tramadol also slowed the recovery rate from the inactivation of Nav1.7 and Nav1.5 and induced stronger use-dependent inhibition. Because the mean plasma concentration of tramadol upon oral administration is lower than its mean blocking concentration of sodium channels in this study, it is unlikely that tramadol in plasma will have an analgesic effect by blocking Nav1.7 or show cardiotoxicity by blocking Nav1.5. However, tramadol could act as a local anesthetic when used at a concentration of several hundred millimoles by intradermal injection and as an antiarrhythmic when injected intravenously at a similar dose, as does lidocaine.

키워드

과제정보

This study was supported by the Research Fund of the Ministry of Science, ICT and Future Planning (NRF-2020R1A2B5B02001804) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1A2B4011333, NRF-2018R1A6A1A03025108).

참고문헌

  1. Altunkaya, H., Ozer, Y., Kargi, E. and Babuccu, O. (2003) Comparison of local anaesthetic effects of tramadol with prilocaine for minor surgical procedures. Br. J. Anaesth. 90, 320-322.  https://doi.org/10.1093/bja/aeg079
  2. Bean, B. P., Cohen, C. J. and Tsien, R. W. (1983) Lidocaine block of cardiac sodium channels. J. Gen. Physiol. 81,613-642. https://doi.org/10.1085/jgp.81.5.613
  3. Beyazova, M., Ozturk, E., Zinnuroglu, M., Gokyar, I., Babacan, A. and Kaya, K. (2011) Effects of perineural tramadol on nerve conduction of sural nerve. Agri 23, 51-56.
  4. Calloe, K., Refaat, M. M., Grubb, S., Wojciak, J., Campagna, J., Thomsen, N. M., Nussbaum, R. L., Scheinman, M. M. and Schmitt, N. (2013) Characterization and mechanisms of action of novel NaV1.5 channel mutations associated with Brugada syndrome. Circ. Arrhythm. Electrophysiol. 6, 177-184. https://doi.org/10.1161/CIRCEP.112.974220
  5. Catterall, W. A., Goldin, A. L. and Waxman, S. G. (2005) International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57,397-409. https://doi.org/10.1124/pr.57.4.4
  6. Chevrier, P., Vijayaragavan, K. and Chahine, M. (2004) Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine. Br. J. Pharmacol. 142, 576-584. https://doi.org/10.1038/sj.bjp.0705796
  7. Choi, J.-H., Kim, R.-E., Cho, Y.-Y. and Choi, J.-S. (2023) Stable expression of human Nav1.5 for high-throughput cardiac safety assessment. Mol. Cell. Toxicol. doi: 10.1007/s13273-023-00331-8 [Online ahead of print].
  8. Choi, J. S., Dib-Hajj, S. D. and Waxman, S. G. (2007) Differential slow inactivation and use-dependent inhibition of Nav1.8 channels contribute to distinct firing properties in IB4+ and IB4- DRG neurons. J. Neurophysiol. 97, 1258-1265. https://doi.org/10.1152/jn.01033.2006
  9. Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M. and Woods, C. G. (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894-898. https://doi.org/10.1038/nature05413
  10. de Lera Ruiz, M. and Kraus, R. L. (2015) Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications. J. Med. Chem. 58, 7093-7118. https://doi.org/10.1021/jm501981g
  11. Dib-Hajj, S. D. and Waxman, S. G. (2019) Sodium channels in human pain disorders: genetics and pharmacogenomics. Annu. Rev. Neurosci. 42, 87-106. https://doi.org/10.1146/annurev-neuro-070918-050144
  12. Dokken, K. and Fairley, P. (2021) Sodium channel blocker toxicity. In: StatPearls. Treasure Island (FL).
  13. Emamhadi, M., Sanaei-Zadeh, H., Nikniya, M., Zamani, N. and Dart, R. C. (2012) Electrocardiographic manifestations of tramadol toxicity with special reference to their ability for prediction of seizures. Am. J. Emerg. Med. 30, 1481-1485. https://doi.org/10.1016/j.ajem.2011.12.009
  14. Faria, J., Barbosa, J., Moreira, R., Queiros, O., Carvalho, F. and DinisOliveira, R. J. (2018) Comparative pharmacology and toxicology of tramadol and tapentadol. Eur. J. Pain 22, 827-844. https://doi.org/10.1002/ejp.1196
  15. Grond, S. and Sablotzki, A. (2004) Clinical pharmacology of tramadol. Clin. Pharmacokinet. 43, 879-923. https://doi.org/10.2165/00003088-200443130-00004
  16. Haeseler, G., Foadi, N., Ahrens, J., Dengler, R., Hecker, H. and Leuwer, M. (2006) Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels. Pain 126, 234-244. https://doi.org/10.1016/j.pain.2006.07.003
  17. Han, C., Themistocleous, A. C., Estacion, M., Dib-Hajj, F. B., Blesneac, I., Macala, L., Fratter, C., Bennett, D. L., Waxman, S. G. and Dib-Hajj, S. D. (2018) The novel activity of carbamazepine as an activation modulator extends from NaV1.7 mutations to the NaV1.8-S242T mutant channel from a patient with painful diabetic neuropathy. Mol. Pharmacol. 94, 1256-1269. https://doi.org/10.1124/mol.118.113076
  18. Leffler, A., Frank, G., Kistner, K., Niedermirtl, F., Koppert, W., Reeh, P. W. and Nau, C. (2012) Local anesthetic-like inhibition of voltage-gated Na(+) channels by the partial mu-opioid receptor agonist buprenorphine. Anesthesiology 116, 1335-1346. https://doi.org/10.1097/ALN.0b013e3182557917
  19. Meents, J. E., Juhasz, K., Stolzle-Feix, S., Peuckmann-Post, V., Rolke, R. and Lampert, A. (2018) The opioid oxycodone use-dependently inhibits the cardiac sodium channel NaV 1.5. Br. J. Pharmacol. 175, 3007-3020. https://doi.org/10.1111/bph.14348
  20. Mert, T., Gunes, Y., Guven, M., Gunay, I. and Gocmen, C. (2003) Differential effects of lidocaine and tramadol on modified nerve impulse by 4-aminopyridine in rats. Pharmacology 69, 68-73. https://doi.org/10.1159/000072358
  21. Mulroy, M. F. (2002) Systemic toxicity and cardiotoxicity from local anesthetics: incidence and preventive measures. Reg. Anesth. Pain Med. 27, 556-561. https://doi.org/10.1097/00115550-200211000-00003
  22. Nakajima, T., Kaneko, Y., Saito, A., Ota, M., Iijima, T. and Kurabayashi, M. (2015) Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome. Heart Rhythm 12, 2296-2304. https://doi.org/10.1016/j.hrthm.2015.05.032
  23. Olschewski, A., Hempelmann, G., Vogel, W. and Safronov, B. V. (2001) Suppression of potassium conductance by droperidol has influence on excitability of spinal sensory neurons. Anesthesiology 94, 280-289. https://doi.org/10.1097/00000542-200102000-00018
  24. Pang, W. W., Mok, M. S., Chang, D. P. and Huang, M. H. (1998) Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Reg. Anesth. Pain Med. 23, 580-583. https://doi.org/10.1016/S1098-7339(98)90085-2
  25. Smyj, R., Wang, X. P. and Han, F. (2013) Tramadol hydrochloride. Profiles Drug Subst. Excip. Relat. Methodol. 38, 463-494. https://doi.org/10.1016/B978-0-12-407691-4.00011-3
  26. Tsai, T. Y., Tsai, Y. C., Wu, S. N. and Liu, Y. C. (2006) Tramadol-induced blockade of delayed rectifier potassium current in NG108-15 neuronal cells. Eur. J. Pain 10, 597-601. https://doi.org/10.1016/j.ejpain.2005.09.001
  27. Wagner, L. E., 2nd, Eaton, M., Sabnis, S. S. and Gingrich, K. J. (1999) Meperidine and lidocaine block of recombinant voltage-dependent Na+ channels: evidence that meperidine is a local anesthetic. Anesthesiology 91, 1481-1490. https://doi.org/10.1097/00000542-199911000-00042
  28. Wang, Q., Li, Z., Shen, J. and Keating, M. T. (1996) Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics 34,9-16. https://doi.org/10.1006/geno.1996.0236
  29. Waxman, S. G. and Dib-Hajj, S. D. (2019) The two sides of NaV1.7: painful and painless channelopathies. Neuron 101, 765-767. https://doi.org/10.1016/j.neuron.2019.02.016
  30. Wolff, M., Olschewski, A., Vogel, W. and Hempelmann, G. (2004) Meperidine suppresses the excitability of spinal dorsal horn neurons. Anesthesiology 100, 947-955. https://doi.org/10.1097/00000542-200404000-00027
  31. Wu, Y. J., Guernon, J., Shi, J., Ditta, J., Robbins, K. J., Rajamani, R., Easton, A., Newton, A., Bourin, C., Mosure, K., Soars, M. G., Knox, R. J., Matchett, M., Pieschl, R. L., Post-Munson, D. J., Wang, S., Herrington, J., Graef, J., Newberry, K., Bristow, L. J., Meanwell, N. A., Olson, R., Thompson, L. A. and Dzierba, C. (2017) Development of new benzenesulfonamides as potent and selective Nav1.7 inhibitors for the treatment of pain. J. Med. Chem. 60, 2513-2525. https://doi.org/10.1021/acs.jmedchem.6b01918
  32. Yu, F. H. and Catterall, W. A. (2003) Overview of the voltage-gated sodium channel family. Genome Biol. 4, 207.