The sigma receptor (R), once considered a subtype of the opioid receptor, is now described as a distinct pharmacological entity. Modulation of N-methyl-D-aspartate receptor (NMDAR) functions by R-1 ligands is well documented, however, its mechanism is not fully understood. Using patch-clamp whole-cell recordings in CA1 pyramidal cells of rat hippocampus and (+)pentazocine, a high affinity R-1 agonist, we found that R-1 activation potentiates NMDAR responses and long-term potentiation (LTP) by preventing a small conductance Ca²⁺-activated K⁺ current (SK channels), known to shunt NMDAR responses, to open. Therefore, the block of SK channels and the resulting increased Ca²⁺ influx through the NMDAR enhances NMDAR responses and LTP. These results emphasize the importance of the R-1 as post-synaptic regulator of synaptic transmission.