Positive feedback control as a key central mechanism for persistent pain. Sensory inputs inducing painful stimuli enter the brain through three major synaptic relays, including the dorsal horn (DH), thalamus and anterior cingulate cortex (ACC). At each synaptic relay, glutamate is the major fast excitatory transmitter. While AMPA and KA receptors mediate most of the synaptic response at resting conditions, NMDA receptors serve as a coincidence detector to enhance synaptic responses in an activity-dependent manner. Long-lasting potentiation is likely to occur at each sensory synapse. Within the ACCs, cortical connections may also undergo plastic changes, and may serve as highest central loci to store unpleasantness or pain. In addition, dorsal horn sensory synapses receive heterosynaptic facilitatory modulation from supraspinal structures, including the forebrain and brainstem. The RVM in the brainstem is likely to serve as a final relay for this descending facilitatory or excitatory modulation. Both homosynaptic and heterosynaptic enhancement will lead central sensory neurons to an enhanced excitatory status, so that a gentle trigger (for example, allodynia) or stimulation can cause massive firing of action potentials and thus cause pain. In the case of central pain, spontaneous activity of neurons in the network itself can also lead to action potential firing and pain.