Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Na_v1.7 and Na_v1.5

Abstract

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.

The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells

“… 36 We found also a negative shift in the V 1/2 of activation, and this was also found by Bok et al for Na v 1.7, but not for Na v 1.5. 36 While our findings are thus largely consistent with the study of Bok et al , our study offers significant advances beyond that study by also including other opioids and AP studies in cardiomyocytes. Action potential studies are of particular relevance because previous studies have suggested that tramadol may impact not only on cardiac depolarization and Na v 1.5 current but also on cardiac repolarization and AP duration.…”

“…In fact, the IC 50 on Na v 1.5 channels that were in a partially fast-inactivated state was now 4.5 ± 1.1 μ m , which is close to therapeutic concentrations (up to 1.14 µ m ). This effect was also documented by Bok et al 36 In the meantime, we also notice that this change is not so obvious in the AP measurements in which the cardiomyocytes have a RMP of around −80 mV. Our result showed that the tramadol-induced d V /d t max reduction is concentration dependent, and tramadol-induced reduction of d V /d t max was only present at 300 µ m in comparison to the baseline condition.…”

“…They found that tramadol reduced Na v 1.5 current, consistent with our findings, with an IC 50 of 0.85 ± 0.04 m m at a −120 mV holding potential. We also used a holding potential of −120 mV, but we found an IC 50 of 0.38 ± 0.03 m m , which is thus 2.2 times smaller than in the study of Bok et al 36 In both studies, the IC 50 decreases upon more depolarized holding potentials indicating that the blocking effect of tramadol is increased in the presence of more inactivated Na v 1.5 channels. This principle is also observed for Na v 1.5 and Na v 1.2 currents in HEK293 cells.…”

“…Of note, the concentration of tramadol required for 50% inhibition of Na v 1.5 currents when measured at a holding potential of −120 mV (IC 50 378.5 ± 33.2 µ m ) was only mildly greater than the concentrations needed to obtain 50% block of TTX-sensitive neuronal sodium currents in rodent neuroblastoma ND7/23 cells (194 ± 9 µ m ) 24 and of rat Na v 1.2 in HEK293 cells (103 ± 8 µ m ). 28 Very recently, Bok et al 36 also tested the effect of tramadol on Na v 1.7 and Na v 1.5 currents in HEK293 cells. They found that tramadol reduced Na v 1.5 current, consistent with our findings, with an IC 50 of 0.85 ± 0.04 m m at a −120 mV holding potential.…”

“… 28 , 36 In our study, the V 1/2 of Na v 1.5 inactivation is slightly more negative under control conditions compared to the study of Bok et al As a result, we might have more inactivated Na v 1.5 channels at −120 mV resulting in a more pronounced inhibition and a shift in IC 50 to lower concentrations compared to the study of Bok et al 36 Moreover, the tramadol-induced negative shift of voltage-gated inactivation and the use-dependent block of Na v 1.5 that we found agree with the findings of Bok et al , 36 and this was also observed for Na v 1.2 current 28 and Na v 1.7. 36 We found also a negative shift in the V 1/2 of activation, and this was also found by Bok et al for Na v 1.7, but not for Na v 1.5. 36 While our findings are thus largely consistent with the study of Bok et al , our study offers significant advances beyond that study by also including other opioids and AP studies in cardiomyocytes.…”