Block of voltage-dependent sodium currents by the substance P receptor antagonist (+/-)-CP-96,345 in neurones cultured from rat cortex.
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 NK1 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 microM 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 nM and 1.3 +/- 0.2 mM respectively. 3. The depression of sodium currents by (+/-)-CP-96,345 (10 microM) 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 microM) and tetrodotoxin (30 nM) 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 NK1 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.
Caeser
M
M
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
Seabrook
G R
GR
Kemp
J A
JA
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004594:Electrophysiology; D005260:Female; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007700:Kinetics; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology
D001713:Biphenyl Compounds; D006993:Hypnotics and Sedatives; D064729:Neurokinin-1 Receptor Antagonists; D015222:Sodium Channels; D013779:Tetrodotoxin; D008012:Lidocaine; C066892:CP 96345