Various studies implicate the anterior cingulate cortex (ACC) in processing pain. Combining whole-cell patch clamp recordings in rat ACC slices and a formalin-induced conditioned place avoidance (F-CPA) behavioral model, the present study was to address the effect of GABA(A) receptors on excitatory transmission to ACC layer V neurons and its possible functional significance related to pain. Removal of GABA(A) inhibition by bicuculline (10 mu M) induced a novel long-lasting response in layer V neurons, which could be blocked by high divalent extracellular Solution and was sensitive to relatively higher rate stimuli. Co-application of NMDA receptor antagonist APV (50 mu M) and non-NMDA receptor antagonist DNQX (10 mu M) completely blocked the responses. Enhancement of inhibition by intra-ACC microinjection of muscimol abolished the acquisition of F-CPA without affecting formalin-induced acute nociceptive responses. These results Suggest that GABA(A) inhibition may be involved in pain-related aversion by Modulating glutamate-mediated excitatory transmission in the ACC. (c) 2005 Elsevier Inc. All rights reserved.