1. The rapid cell death of cortical neurons in serum-free culture was rescued by the condition medium from the high-density culture, but not by brain-derived neurotrophic factor or basic fibroblast growth factor. 2. Similar rescue was observed by the addition of (-)BPAP, an impulse enhancer, and (+)-pentazocine, a sigma receptor agonist. These actions were blocked by BD1063, a sigma receptor antagonist. 3. (-)BPAP showed a weak displacement activity in the [3H]pentazocine binding to synaptic membranes from rat cerebral cortex. 4. These findings suggest that (-)BPAP and (+)-pentazocine have unique survival activity on cortical neurons through sigma receptors.