Over a million North Americans suffer traumatic brain injury (TBI) each year. Of these, over 60,000 die and more than 80,000 suffer permanent disability. However no pharmacological agent can yet improve TBI. Primary TBI can cause recurring spreading depression (SD), a massive depolarization of neurons and glia lasting 1-2 min that increases metabolic stress and might promote secondary TBI. Using live rat neocortical slices we have shown that within minutes of injury SD exacerbates 1° TBI evoked by stabbing the slice (SFN abstr. 210.10, 2001). It may therefore be possible to improve TBI outcome by blocking SD immediately following a primary injury. Dextromethorphan (DM) is one of several σ1R agonists that block SD, an effect independent of NMDA receptor antagonism (SFN abstr. 332.6, 2001). Here we show that bath application of 30 μM DM or 100 μM BD-1063 (another σ1R ligand) can stop TBI-related SD (n=13/13, n=11/11 slices respectively). Coapplying the σ1R antagonist (+)-3-PPP (100 μM) reverses the DM effect...