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Inhibition of Voltage‐Sensitive Sodium Channels by the Cannabinoid 1 Receptor Antagonist AM 251 in Mammalian Brain
Author(s) -
Liao Chengyong,
Zheng Jian,
David Laurence S.,
Nicholson Russell A.
Publication year - 2004
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2004.pto940204.x
Subject(s) - veratridine , batrachotoxin , sodium channel , chemistry , cannabinoid , neurotoxin , tetrodotoxin , inhibitory postsynaptic potential , radioligand , depolarization , excitatory postsynaptic potential , antagonist , pharmacology , biophysics , sodium , receptor , biochemistry , endocrinology , biology , organic chemistry
The cannabinoid 1 receptor antagonist AM 251 is known to block the inhibitory effects of endocannabinoids and synthetic cannabinoid agonists on transmitter release through an action at presynaptic cannabinoid 1 receptors in brain. We examined the ability of AM 251 to inhibit sodium channel‐dependent functions and the binding of [ 3 H]batrachotoxinin A 20‐α‐benzoate to sodium channels in mouse brain synaptic preparations. Depolarization of synaptoneurosomes by the sodium channel site 2‐specific neurotoxin veratridine, which is abolished by tetrodotoxin, was found to be inhibited in a concentration‐dependent fashion by AM 251 (IC 50 =8.9 μM). Veratridine‐dependent (tetrodotoxin suppressible) release, of L‐glutamic acid and GABA from synaptosomes was also reduced by AM 251 [IC 50 s=8.5 μM (L‐glutamic acid), 9.2 μM (GABA)]. The binding of the radioligand [ 3 H]batrachotoxinin A 20‐α‐benzoate to site 2 on sodium channels was displaced by AM 251 (IC 50 =11.2 μM). Scatchard analysis of binding showed that at its IC 50 , AM 251 increased (by 2.3 times) the K D of radioligand without altering B max , suggesting a competitive mechanism of inhibition by AM 251. Kinetic experiments indicated that AM 251 inhibits equilibrium binding by allosterically accelerating the dissociation of the [ 3 H]‐batrachotoxinin A 20‐α‐benzoate:sodium channel complex. Our data suggest that micromolar concentrations of AM 251 are capable of reducing neuronal excitability and inhibiting release of excitatory and inhibitory transmitters through blockade of voltage‐sensitive sodium channels in brain.