Chronic pain is a major medical problem that is resistant to conventional medical intervention. It also causes emotional changes such as anxiety and fear. Furthermore, anxiety or fear often enhances the suffering of pain. Based on recent studies, I propose chronic anxiety triggered by injury or chronic pain is mediated through presynaptic long-term potentiation (LTP) in the anterior cingulate cortex (ACC), a key cortical region for pain perception. Conversely, NMDA receptor-dependent postsynaptic LTP plays a more important role in behavioral sensitization in chronic pain. Thus, postsynaptic and presynaptic LTP in ACC neurons are likely the key cellular mechanisms for causing chronic pain and its associated anxiety, respectively. This suggests potential targets for treating chronic pain and related anxiety.