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Tranexamic acid evokes pain by modulating neuronal excitability in the spinal dorsal horn.

Ohashi N, Sasaki M, Ohashi M, Kamiya Y, Baba H, Kohno T - Sci Rep (2015)

Bottom Line: Tranexamic acid (TXA) is an antifibrinolytic agent widely used to reduce blood loss during surgery.However, the effect of TXA on spinal dorsal horn neurons remain poorly understood.These results indicated that TXA produces pain by inhibiting GABAA and glycine receptors in the spinal dorsal horn.

View Article: PubMed Central - PubMed

Affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, 951-8510 Japan.

ABSTRACT
Tranexamic acid (TXA) is an antifibrinolytic agent widely used to reduce blood loss during surgery. However, a serious adverse effect of TXA is seizure due to inhibition of γ-aminobutyric acid (GABA) and glycine receptors in cortical neurons. These receptors are also present in the spinal cord, and antagonism of these receptors in spinal dorsal horn neurons produces pain-related phenomena, such as allodynia and hyperalgesia, in experimental animals. Moreover, some patients who are injected intrathecally with TXA develop severe back pain. However, the effect of TXA on spinal dorsal horn neurons remain poorly understood. Here, we investigated the effects of TXA by using behavioral measures in rats and found that TXA produces behaviors indicative of spontaneous pain and mechanical allodynia. We then performed whole-cell patch-clamp experiments that showed that TXA inhibits GABAA and glycine receptors in spinal dorsal horn neurons. Finally, we also showed that TXA facilitates activation of the extracellular signal-regulated kinase in the spinal cord. These results indicated that TXA produces pain by inhibiting GABAA and glycine receptors in the spinal dorsal horn.

No MeSH data available.


Related in: MedlinePlus

Tranexamic acid (TXA) facilitates excitatory glutamatergic transmission.(A) TXA (1 mM, 2 min) has no effect on the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, TXA significantly increases sEPSC frequency (n = 7). Moreover, TXA induced inward currents (>5 pA) in all recorded neurons (n = 7). (B) TXA (1 mM, 2 min) has no effect on mEPSC amplitude or frequency (n = 7). (C) TXA has no effect on the amplitude of Aδ fiber-evoked monosynaptic EPSCs. In contrast, TXA significantly increases the integrated area of Aδ fiber-evoked polysynaptic EPSCs (n = 7). (D) TXA has no effect on the amplitude of C fiber-evoked monosynaptic EPSCs. In contrast, TXA significantly increases the integrated area of C fiber-evoked polysynaptic EPSCs (n = 7). Holding potential = −70 mV for all recordings. **P < 0.01 by paired t-test.
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f5: Tranexamic acid (TXA) facilitates excitatory glutamatergic transmission.(A) TXA (1 mM, 2 min) has no effect on the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, TXA significantly increases sEPSC frequency (n = 7). Moreover, TXA induced inward currents (>5 pA) in all recorded neurons (n = 7). (B) TXA (1 mM, 2 min) has no effect on mEPSC amplitude or frequency (n = 7). (C) TXA has no effect on the amplitude of Aδ fiber-evoked monosynaptic EPSCs. In contrast, TXA significantly increases the integrated area of Aδ fiber-evoked polysynaptic EPSCs (n = 7). (D) TXA has no effect on the amplitude of C fiber-evoked monosynaptic EPSCs. In contrast, TXA significantly increases the integrated area of C fiber-evoked polysynaptic EPSCs (n = 7). Holding potential = −70 mV for all recordings. **P < 0.01 by paired t-test.

Mentions: GABAA and glycine receptor antagonists affect excitatory glutamatergic transmission33. Therefore, in the next set of experiments, we tested the effects of TXA on sEPSCs and mEPSCs, which represent glutamatergic transmission. In the presence of TXA, the mean sEPSC amplitude was not affected (control, 10.0 ± 4.7; TXA, 9.9 ± 4.3 pA, 100.6 ± 7.0% of control; n = 7, P = 0.97; Fig. 5A). However, the mean sEPSC frequency in the presence of TXA significantly increased from 7.3 ± 4.2 to 10.2 ± 5.1 Hz (144.0 ± 2.9% of control, n = 7, P < 0.01; Fig. 5A). Moreover, TXA induced an inward current (>5 pA) in all recording neurons (n = 7; Fig. 5A). The average peak amplitude of the TXA-induced inward current was 6.0 ± 8.1 pA. In contrast, neither the mean mEPSC amplitude (control, 7.5 ± 1.6; TXA, 7.5 ± 1.6 pA, 100.2 ± 3.6% of control; n = 7, P = 0.99; Fig. 5B) nor frequency (control, 7.2 ± 3.0; TXA, 7.2 ± 3.0 Hz, 100.5 ± 1.9% of control; n = 7, P = 0.98) was affected in the presence of TXA with mEPSCs isolated by adding TTX. Furthermore, the TXA-induced inward current was suppressed by adding TTX in all recording neurons (n = 7; Fig. 5B). These results suggest that TXA does not affect the presynaptic terminals of excitatory neurons, because TXA has no effect on the frequency of mEPSCs. In contrast, our results instead suggest that TXA acts on the somata of excitatory neurons, and by reducing inhibition facilitates glutamate release, which causes neuronal excitation, because TXA increases inward current and the frequency of sEPSCs but does not affect sEPSC/mEPSC amplitude.


Tranexamic acid evokes pain by modulating neuronal excitability in the spinal dorsal horn.

Ohashi N, Sasaki M, Ohashi M, Kamiya Y, Baba H, Kohno T - Sci Rep (2015)

Tranexamic acid (TXA) facilitates excitatory glutamatergic transmission.(A) TXA (1 mM, 2 min) has no effect on the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, TXA significantly increases sEPSC frequency (n = 7). Moreover, TXA induced inward currents (>5 pA) in all recorded neurons (n = 7). (B) TXA (1 mM, 2 min) has no effect on mEPSC amplitude or frequency (n = 7). (C) TXA has no effect on the amplitude of Aδ fiber-evoked monosynaptic EPSCs. In contrast, TXA significantly increases the integrated area of Aδ fiber-evoked polysynaptic EPSCs (n = 7). (D) TXA has no effect on the amplitude of C fiber-evoked monosynaptic EPSCs. In contrast, TXA significantly increases the integrated area of C fiber-evoked polysynaptic EPSCs (n = 7). Holding potential = −70 mV for all recordings. **P < 0.01 by paired t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544020&req=5

f5: Tranexamic acid (TXA) facilitates excitatory glutamatergic transmission.(A) TXA (1 mM, 2 min) has no effect on the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, TXA significantly increases sEPSC frequency (n = 7). Moreover, TXA induced inward currents (>5 pA) in all recorded neurons (n = 7). (B) TXA (1 mM, 2 min) has no effect on mEPSC amplitude or frequency (n = 7). (C) TXA has no effect on the amplitude of Aδ fiber-evoked monosynaptic EPSCs. In contrast, TXA significantly increases the integrated area of Aδ fiber-evoked polysynaptic EPSCs (n = 7). (D) TXA has no effect on the amplitude of C fiber-evoked monosynaptic EPSCs. In contrast, TXA significantly increases the integrated area of C fiber-evoked polysynaptic EPSCs (n = 7). Holding potential = −70 mV for all recordings. **P < 0.01 by paired t-test.
Mentions: GABAA and glycine receptor antagonists affect excitatory glutamatergic transmission33. Therefore, in the next set of experiments, we tested the effects of TXA on sEPSCs and mEPSCs, which represent glutamatergic transmission. In the presence of TXA, the mean sEPSC amplitude was not affected (control, 10.0 ± 4.7; TXA, 9.9 ± 4.3 pA, 100.6 ± 7.0% of control; n = 7, P = 0.97; Fig. 5A). However, the mean sEPSC frequency in the presence of TXA significantly increased from 7.3 ± 4.2 to 10.2 ± 5.1 Hz (144.0 ± 2.9% of control, n = 7, P < 0.01; Fig. 5A). Moreover, TXA induced an inward current (>5 pA) in all recording neurons (n = 7; Fig. 5A). The average peak amplitude of the TXA-induced inward current was 6.0 ± 8.1 pA. In contrast, neither the mean mEPSC amplitude (control, 7.5 ± 1.6; TXA, 7.5 ± 1.6 pA, 100.2 ± 3.6% of control; n = 7, P = 0.99; Fig. 5B) nor frequency (control, 7.2 ± 3.0; TXA, 7.2 ± 3.0 Hz, 100.5 ± 1.9% of control; n = 7, P = 0.98) was affected in the presence of TXA with mEPSCs isolated by adding TTX. Furthermore, the TXA-induced inward current was suppressed by adding TTX in all recording neurons (n = 7; Fig. 5B). These results suggest that TXA does not affect the presynaptic terminals of excitatory neurons, because TXA has no effect on the frequency of mEPSCs. In contrast, our results instead suggest that TXA acts on the somata of excitatory neurons, and by reducing inhibition facilitates glutamate release, which causes neuronal excitation, because TXA increases inward current and the frequency of sEPSCs but does not affect sEPSC/mEPSC amplitude.

Bottom Line: Tranexamic acid (TXA) is an antifibrinolytic agent widely used to reduce blood loss during surgery.However, the effect of TXA on spinal dorsal horn neurons remain poorly understood.These results indicated that TXA produces pain by inhibiting GABAA and glycine receptors in the spinal dorsal horn.

View Article: PubMed Central - PubMed

Affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, 951-8510 Japan.

ABSTRACT
Tranexamic acid (TXA) is an antifibrinolytic agent widely used to reduce blood loss during surgery. However, a serious adverse effect of TXA is seizure due to inhibition of γ-aminobutyric acid (GABA) and glycine receptors in cortical neurons. These receptors are also present in the spinal cord, and antagonism of these receptors in spinal dorsal horn neurons produces pain-related phenomena, such as allodynia and hyperalgesia, in experimental animals. Moreover, some patients who are injected intrathecally with TXA develop severe back pain. However, the effect of TXA on spinal dorsal horn neurons remain poorly understood. Here, we investigated the effects of TXA by using behavioral measures in rats and found that TXA produces behaviors indicative of spontaneous pain and mechanical allodynia. We then performed whole-cell patch-clamp experiments that showed that TXA inhibits GABAA and glycine receptors in spinal dorsal horn neurons. Finally, we also showed that TXA facilitates activation of the extracellular signal-regulated kinase in the spinal cord. These results indicated that TXA produces pain by inhibiting GABAA and glycine receptors in the spinal dorsal horn.

No MeSH data available.


Related in: MedlinePlus