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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) decreases the amplitude of GABAergic and glycinergic mIPSCs without changes in frequency.(A) TXA (1 mM, 2 min) significantly decreases the amplitude of miniature inhibitory postsynaptic currents (mIPSCs) and shifts the cumulative distribution of the amplitudes to the left. In contrast, TXA has no effect on the mIPSC frequency or cumulative distribution of the inter-event intervals (n = 7). Downward arrows indicate outtakes of the top trace shown on an expanded timescale. Heavy horizontal bars show periods of drug application. (B) In the presence of strychnine (2 μM), a glycine receptor antagonist, TXA (1 mM, 2 min) significantly decreases GABAergic mIPSC amplitude. However, TXA has no effect on GABAergic mIPSC frequency (n = 7). (C) In the presence of bicuculline (20 μM), a GABAA receptor antagonist, TXA (1 mM, 2 min) significantly decreases the amplitude of glycinergic mIPSCs. However, TXA has no effect on the frequency of glycinergic mIPSCs (n = 7). Holding potential = 0 mV for all recordings. **P < 0.01 by paired t-test.
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f2: Tranexamic acid (TXA) decreases the amplitude of GABAergic and glycinergic mIPSCs without changes in frequency.(A) TXA (1 mM, 2 min) significantly decreases the amplitude of miniature inhibitory postsynaptic currents (mIPSCs) and shifts the cumulative distribution of the amplitudes to the left. In contrast, TXA has no effect on the mIPSC frequency or cumulative distribution of the inter-event intervals (n = 7). Downward arrows indicate outtakes of the top trace shown on an expanded timescale. Heavy horizontal bars show periods of drug application. (B) In the presence of strychnine (2 μM), a glycine receptor antagonist, TXA (1 mM, 2 min) significantly decreases GABAergic mIPSC amplitude. However, TXA has no effect on GABAergic mIPSC frequency (n = 7). (C) In the presence of bicuculline (20 μM), a GABAA receptor antagonist, TXA (1 mM, 2 min) significantly decreases the amplitude of glycinergic mIPSCs. However, TXA has no effect on the frequency of glycinergic mIPSCs (n = 7). Holding potential = 0 mV for all recordings. **P < 0.01 by paired t-test.

Mentions: We next investigated the mechanism of TXA action on SG neurons using the whole-cell patch-clamp technique. As it has been reported that TXA inhibits GABA and glycine receptors in the brain141516, we examined the effect of TXA on inhibitory synaptic transmission pre- and/or postsynaptically. mIPSCs were isolated by adding TTX (1 μM) to the perfusate. In the presence of TXA (1 mM, 2 min), mean mIPSC amplitude decreased from 12.4 ± 7.1 to 7.0 ± 2.8 pA (59.9 ± 8.5% of control, n = 7, P < 0.01; Fig. 2A). Conversely, mean mIPSC frequency was unaffected by TXA (control, 4.4 ± 1.5; TXA, 4.4 ± 1.4 Hz, 99.4 ± 1.4% of control; n = 7, P = 0.98). Figure 2A (right panel) shows the effects of TXA on the cumulative distribution of the amplitudes and inter-event intervals of the mIPSCs. When compared to the control using the Kolmogorov-Smirnov test, superfusion with TXA increased the proportion of mIPSCs with significantly smaller amplitudes. However, TXA had no effect on the cumulative inter-event interval distribution of the mIPSCs over the recording period. These findings indicate that the TXA-induced decrease in inhibitory activity is postsynaptic in origin.


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) decreases the amplitude of GABAergic and glycinergic mIPSCs without changes in frequency.(A) TXA (1 mM, 2 min) significantly decreases the amplitude of miniature inhibitory postsynaptic currents (mIPSCs) and shifts the cumulative distribution of the amplitudes to the left. In contrast, TXA has no effect on the mIPSC frequency or cumulative distribution of the inter-event intervals (n = 7). Downward arrows indicate outtakes of the top trace shown on an expanded timescale. Heavy horizontal bars show periods of drug application. (B) In the presence of strychnine (2 μM), a glycine receptor antagonist, TXA (1 mM, 2 min) significantly decreases GABAergic mIPSC amplitude. However, TXA has no effect on GABAergic mIPSC frequency (n = 7). (C) In the presence of bicuculline (20 μM), a GABAA receptor antagonist, TXA (1 mM, 2 min) significantly decreases the amplitude of glycinergic mIPSCs. However, TXA has no effect on the frequency of glycinergic mIPSCs (n = 7). Holding potential = 0 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

f2: Tranexamic acid (TXA) decreases the amplitude of GABAergic and glycinergic mIPSCs without changes in frequency.(A) TXA (1 mM, 2 min) significantly decreases the amplitude of miniature inhibitory postsynaptic currents (mIPSCs) and shifts the cumulative distribution of the amplitudes to the left. In contrast, TXA has no effect on the mIPSC frequency or cumulative distribution of the inter-event intervals (n = 7). Downward arrows indicate outtakes of the top trace shown on an expanded timescale. Heavy horizontal bars show periods of drug application. (B) In the presence of strychnine (2 μM), a glycine receptor antagonist, TXA (1 mM, 2 min) significantly decreases GABAergic mIPSC amplitude. However, TXA has no effect on GABAergic mIPSC frequency (n = 7). (C) In the presence of bicuculline (20 μM), a GABAA receptor antagonist, TXA (1 mM, 2 min) significantly decreases the amplitude of glycinergic mIPSCs. However, TXA has no effect on the frequency of glycinergic mIPSCs (n = 7). Holding potential = 0 mV for all recordings. **P < 0.01 by paired t-test.
Mentions: We next investigated the mechanism of TXA action on SG neurons using the whole-cell patch-clamp technique. As it has been reported that TXA inhibits GABA and glycine receptors in the brain141516, we examined the effect of TXA on inhibitory synaptic transmission pre- and/or postsynaptically. mIPSCs were isolated by adding TTX (1 μM) to the perfusate. In the presence of TXA (1 mM, 2 min), mean mIPSC amplitude decreased from 12.4 ± 7.1 to 7.0 ± 2.8 pA (59.9 ± 8.5% of control, n = 7, P < 0.01; Fig. 2A). Conversely, mean mIPSC frequency was unaffected by TXA (control, 4.4 ± 1.5; TXA, 4.4 ± 1.4 Hz, 99.4 ± 1.4% of control; n = 7, P = 0.98). Figure 2A (right panel) shows the effects of TXA on the cumulative distribution of the amplitudes and inter-event intervals of the mIPSCs. When compared to the control using the Kolmogorov-Smirnov test, superfusion with TXA increased the proportion of mIPSCs with significantly smaller amplitudes. However, TXA had no effect on the cumulative inter-event interval distribution of the mIPSCs over the recording period. These findings indicate that the TXA-induced decrease in inhibitory activity is postsynaptic in origin.

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