Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons
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Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons. / Bräu, M E; Dreimann, M; Olschewski, A; Vogel, W; Hempelmann, G.
In: ANESTHESIOLOGY, Vol. 94, No. 1, 01.01.2001, p. 137-44.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons
AU - Bräu, M E
AU - Dreimann, M
AU - Olschewski, A
AU - Vogel, W
AU - Hempelmann, G
PY - 2001/1/1
Y1 - 2001/1/1
N2 - BACKGROUND: Tetrodotoxin-resistant Na(+) channels play an important role in generation and conduction of nociceptive discharges in peripheral endings of small-diameter axons of the peripheral nervous system. Pathophysiologically, these channels may produce ectopic discharges in damaged nociceptive fibers, leading to neuropathic pain syndromes. Systemically applied Na(+) channel--blocking drugs can alleviate pain, the mechanism of which is rather unresolved. The authors investigated the effects of some commonly used drugs, i.e., lidocaine, mexiletine, carbamazepine, amitriptyline, memantine, and gabapentin, on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglia.METHODS: Tetrodotoxin-resistant Na(+) currents were recorded in the whole-cell configuration of the patch-clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Half-maximal blocking concentrations were derived from concentration-inhibition curves at different holding potentials (-90, -70, and -60 mV).RESULTS: Lidocaine, mexiletine, and amitriptyline reversibly blocked tetrodotoxin-resistant Na(+) currents in a concentration- and use-dependent manner. Block by carbamazepine and memantine was not use-dependent at 2 Hz. Gabapentin had no effect at concentrations of up to 3 mm. Depolarizing the membrane potential from -90 mV to -60 mV reduced the available Na(+) current only by 23% but increased the sensitivity of the channels to the use-dependent blockers approximately fivefold. The availability curve of the current was shifted by 5.3 mV to the left in 300 microm lidocaine.CONCLUSIONS: Less negative membrane potential and repetitive firing have little effect on tetrodotoxin-resistant Na(+) current amplitude but increase their sensitivity to lidocaine, mexiletine, and amitriptyline so that concentrations after intravenous administration of these drugs can impair channel function. This may explain alleviation from pain by reducing firing frequency in ectopic sites without depressing central nervous or cardiac excitability.
AB - BACKGROUND: Tetrodotoxin-resistant Na(+) channels play an important role in generation and conduction of nociceptive discharges in peripheral endings of small-diameter axons of the peripheral nervous system. Pathophysiologically, these channels may produce ectopic discharges in damaged nociceptive fibers, leading to neuropathic pain syndromes. Systemically applied Na(+) channel--blocking drugs can alleviate pain, the mechanism of which is rather unresolved. The authors investigated the effects of some commonly used drugs, i.e., lidocaine, mexiletine, carbamazepine, amitriptyline, memantine, and gabapentin, on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglia.METHODS: Tetrodotoxin-resistant Na(+) currents were recorded in the whole-cell configuration of the patch-clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Half-maximal blocking concentrations were derived from concentration-inhibition curves at different holding potentials (-90, -70, and -60 mV).RESULTS: Lidocaine, mexiletine, and amitriptyline reversibly blocked tetrodotoxin-resistant Na(+) currents in a concentration- and use-dependent manner. Block by carbamazepine and memantine was not use-dependent at 2 Hz. Gabapentin had no effect at concentrations of up to 3 mm. Depolarizing the membrane potential from -90 mV to -60 mV reduced the available Na(+) current only by 23% but increased the sensitivity of the channels to the use-dependent blockers approximately fivefold. The availability curve of the current was shifted by 5.3 mV to the left in 300 microm lidocaine.CONCLUSIONS: Less negative membrane potential and repetitive firing have little effect on tetrodotoxin-resistant Na(+) current amplitude but increase their sensitivity to lidocaine, mexiletine, and amitriptyline so that concentrations after intravenous administration of these drugs can impair channel function. This may explain alleviation from pain by reducing firing frequency in ectopic sites without depressing central nervous or cardiac excitability.
KW - Amitriptyline
KW - Analgesics
KW - Anesthetics, Local
KW - Animals
KW - Cells, Cultured
KW - Diethylcarbamazine
KW - Drug Interactions
KW - Electric Stimulation
KW - Lidocaine
KW - Memantine
KW - Membrane Potentials
KW - Mexiletine
KW - Neurons, Afferent
KW - Patch-Clamp Techniques
KW - Rats
KW - Rats, Wistar
KW - Sodium Channel Blockers
KW - Sodium Channels
KW - Tetrodotoxin
M3 - SCORING: Journal article
C2 - 11135733
VL - 94
SP - 137
EP - 144
JO - ANESTHESIOLOGY
JF - ANESTHESIOLOGY
SN - 0003-3022
IS - 1
ER -