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Block of voltage‐dependent sodium currents by the substance P receptor antagonist (±)‐CP‐96,345 in neurones cultured from rat cortex
Author(s) -
Caeser Manfred,
Seabrook Guy R.,
Kemp John A.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13708.x
Subject(s) - tetrodotoxin , sodium channel , chemistry , sodium channel blocker , stimulation , sodium , antagonist , receptor antagonist , patch clamp , endocrinology , receptor , biophysics , medicine , electrophysiology , pharmacology , anesthesia , biology , biochemistry , organic chemistry
1 Whole cell patch clamp recordings of voltage‐ and tetrodotoxin‐sensitive Na + currents were made from cultured rat neocortical neurones (E18). The effects of the non‐peptide NK 1 receptor antagonist, (±)‐CP‐96,345 on Na + currents was examined, relative to the effect of the local anaesthetic lignocaine and tetrodotoxin. 2 Sodium currents were reversibly depressed by bath application of (±)‐CP‐96,345 with a half‐maximally effective concentration of 18 ± 2 μ m at a stimulation frequency of 0.1 Hz. Likewise the concentrations required to half‐maximally inhibit sodium currents by tetrodotoxin and lignocaine were 10 ± 2 n m and 1.3 ± 0.2 m m respectively. 3 The depression of sodium currents by (±)‐CP‐96,345 (10 μ m ) was use‐dependent in that raising the stimulus frequency from 0.1 Hz to 10 Hz further decreased the magnitude of sodium currents from 60 ± 5% to 37 ± 5% of control values respectively. Similarly, the depression of sodium currents by lignocaine (500 μ m ) and tetrodotoxin (30 n m ) was also accentuated by raising the stimulus frequency from 0.1 Hz to 10 Hz. 4 The effect of (±)‐CP‐96,345 was not associated with a change in either the activation or steady‐state inactivation characteristics of these currents, suggesting that its mechanism of action was via open channel blockade. 5 These data demonstrate that in addition to antagonizing NK 1 receptors, (±)‐CP‐96,345 also acts as a channel blocker on sodium channels at micromolar concentrations, an effect which should be taken into consideration when examining the antinociceptive or anti‐inflammatory action of this compound.