There is substantial evidence supporting the notion that the primary somatosensory (S1) cortex is an important structure involved in the perceptional component of pain. However, investigations have mainly focused on other pain-related formations, and few reports have been provided to investigate the synaptic plasticity in the S1 cortex in response to persistent pain. In the present study, we report that bee venom (BV) injection triggered an imbalance between excitatory and inhibitory synaptic transmission in the S1 cortex in rats. Using multi-electrode array (MED-64) recording, we found that BV-induced persistent inflammatory pain led to temporal and spatial enhancement of synaptic plasticity. Moreover, slice patch clamp recordings on identified pyramidal neurons demonstrated that BV injection increased presynaptic and postsynaptic transmission in excitatory synapses and reduced postsynaptic transmission in inhibitory synapses in the layer II/III neurons within the S1 cortex. In immunohistochemistry and western blot sections, the distribution and expression of total AMPA receptor subunits and GABA were unaffected, while the membrane fractions of GluR2 and GABA were decreased, and their cytosolic fractions were increased on the contrary. The change of GluR1 was opposite to that of GluR2, and GluR3 did not change significantly. Our studies therefore provide direct evidence for both presynaptic and postsynaptic changes in synapses within the S1 cortex in persistent nociception, which are probably related to the membrane trafficking of GluR1, GluR2 and GABA. PERSPECTIVE: Increased synaptic plasticity was detected in S1 following peripheral nociception, with enhanced excitatory and decreased inhibitory synaptic transmissions. Increased GluR1, while reduced GABAα1 and GluR2 membrane trafficking were detected. Therefore, the disrupted excitatory/inhibitory balance in transmissions is involved in nociception processing; and S1 can be a potential antinociceptive site.