Results: cOA stereoselectively inhibited specific binding of toxin to VGSC (inhibitor concentration that displaces 50% of specifically bound radioligand, 39.5 M). cOA increased (4؋) the K d of toxin binding without affecting its binding maximum. Rate of dissociation of radioligand was increased without altering association kinetics, suggesting an allosteric effect (indirect competition at site 2 on VGSC). cOA blocked tetrodotoxin-sensitive sodium currents (maximal effect and affinity were significantly greater at depolarized potentials; P < 0.01). Between 3.2 and 64 M, the block was concentration-dependent and saturable, but cOA did not alter the V 50 for activation curves or the measured reversal potential (P > 0.05). Inactivation curves were significantly shifted in the hyperpolarizing direction by cOA (maximum, ؊15.4 ؎ 0.9 mV at 32 M). cOA (10 M) slowed recovery from inactivation, with increasing from 3.7 ؎ 0.4 ms to 6.4 ؎ 0.5 ms (P < 0.001). cOA did not produce frequencydependent facilitation of block (up to 10 Hz). Conclusions: These effects (and the capacity of oleamide to modulate ␥-aminobutyric acid A receptors in earlier studies) are strikingly similar to those of a variety of anesthetics. Oleamide may represent an endogenous ligand for depressant drug sites in mammalian brain
