Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels

Abstract

Lidocaine-like sodium channel blocking drugs provide pain relief either by interrupting impulse conduction in neurons when applied locally in high concentrations or, when given systemically, by suppressing high-frequency ectopic discharges due to preferential drug binding to inactivated channel states. Lidocaine-like actions of opioids have frequently been demonstrated clinically. However, drug binding to resting and inactivated channel conformations has been studied systematically only in the case of meperidine. The aim of this in vitro study was to investigate the effects of four currently used opioids on heterologously expressed neuronal (NaV(1.2)) voltage-gated sodium channels. Block of sodium currents was studied at hyperpolarized holding potentials and at depolarized potentials inducing either fast- or slow-inactivation. Sufentanil, fentanyl and tramadol but not morphine reversibly suppressed sodium inward currents at high concentrations (half-maximum blocking concentrations (IC50) 49+/-4, 141+/-6 and 103+/-8 microM) when depolarizations were started from hyperpolarized holding potentials. Short depolarizations inducing fast-inactivation and long prepulses inducing slow-inactivation significantly (*p < or = 0.001) increased the blocking potency for these opioids. 15% slow inactivated channels reduced the respective IC50 values to 5+/-3, 12+/-2 and 21+/-2 microM. These results show that: (1) Sufentanil, fentanyl and tramadol block voltage-gated sodium channels with half-maximum inhibitory concentrations similar to the IC50 reported for meperidine. (2) Slow inactivation--a physiological mechanism to suppress ectopic activity in response to slow shifts in membrane potential--increases binding affinity for sufentanil, fentanyl and tramadol. (3) Morphine has no such effects.

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

“…Abnormal activity expressed by these afferents is suppressed by pregabalin, duloxetine, and tramadol (Haeseler et al. 2006; Wang et al. 2010; Chen et al.…”

Spinal and peripheral adenosine A1 receptors contribute to antinociception by tramadol in the formalin test in mice

“…It is conceivable that peripherally administered tramadol might inhibit peripheral 5-HT reuptake (Raffa et al, 1992) leading to increased extracellular 5-HT, 5-HT 7 receptor activation on sensory afferents, generation of intracellular cyclic AMP, extracellular efflux of adenosine with a subsequent activation of extracellular A 1 receptors, but this possibility needs to be explored experimentally. Additional peripheral effects of tramadol such as local anesthetic properties and NMDA and TRPV1 receptor interactions may also contribute to local antinociception (Haeseler et al, 2006;Hara et al, 2005;Marincsák et al, 2008), but it is not clear how such actions would involve A 1 receptors.…”

“…Furthermore, tramadol is now recognized to interact with additional cellular targets, such as Na + channels (Haeseler et al, 2006), N-methyl-D-aspartate (NMDA) receptors (Hara et al, 2005), and transient receptor potential vanilloid-1 (TRPV1) receptors (Marincsák et al, 2008), and such actions also may contribute to antinociception, particularly when tramadol is given locally and higher local tissue concentrations occur.…”

O efeito analgésico de tramadol não é mediado por receptores opioides na dor de ratos no pós‐operatório imediato

“…[4][5][6]29,30 Os mecanismos envolvidos nessa ação periférica ainda não são bem compreendidos. Há relatos de efeito anti-inflamatório fraco e efeito dependente de cálcio para tramadol.…”

“…3 Além disso, apresenta efeito analgésico nos nervos periféricos que, em parte, é semelhante ao de anestésico local. [4][5][6] O efeito analgésico periférico de tramadol também foi identificado em humanos após infiltração para extração de terceiro molar, procedimentos cirúrgicos menores em crianças e como adjuvante aos anestésicos locais para reduzir a dor no pós-operatório. [7][8][9][10][11][12] Os receptores opioides periféricos há muito foram descritos e seu papel na analgesia em animais e humanos já foi demonstrado, 13---20 …”