AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission and play a critical role in synaptic plasticity in the CNS. In adult neurons, most AMPARs have low Ca2+ permeability due to GluR2 subunit expression. Cumulative evidence indicates that AMPAR subunit composition is not static and subject to change during activity-dependent plasticity. Here, we studied how the trafficking of AMPARs is changed in dorsal horn (DH) neurons of spinal cord during persistent pain produced by peripheral inflammation. Persistent peripheral inflammation was induced by complete Freund’s adjuvant (CFA, 100 μl), injected subcutaneously into the plantar side of one hind paw of the deeply isoflurane-anesthetized rats. The animals were used in accordance with protocols that were approved by the Animal Care and Use Committee at the Bogomoletz Institute of Physiology and were consistent with the ethical guidelines of the National Institutes of Health and the International Association for the Study of Pain. AMPAR functioning was investigated using whole-cell patch-clamp recording combined with Ca2+ imaging. We found that peripheral inflammation increases the functional expression of Ca2+-permeable AMPARs in both the synaptic and extrasynaptic membranes of DH neurons. Peripheral inflammation promotes internalization of GluR2 subunits from the synapses of DH neurons during the maintenance period of CFA-induced persistent inflammatory pain (Park et al., 2009). At the same time, a dramatic increase in the functional expression of GluR1-containing Ca2+-permeable AMPARs was observed in the extrasynaptic plasma membrane in lamina II DH neurons. This increase occurred only in SG neurons characterized by intrinsic tonic firing properties, but not in those exhibiting a strong adaptation (Kopach et al., 2011). Altogether, our results demonstrate that persistent inflammation increases the number of Ca2+-permeable AMPARs in both the synaptic and extrasynaptic membranes and their proportion within the entire AMPARs population in DH neurons. That leads to increased Ca2+ influx in the neurons resulting in increased neuron excitability and altered synaptic efficacy during persistent inflammatory pain.