A model for the role of cingulate-spinal projection pathways in pain regulation and their synaptic plasticity after nerve injury. A, A diagram shows the spinal-cortex-spinal circuit containing the spinal cord dorsal horn and ACC in the transmission and modulation of sensory information in chronic pain conditions. Through the thalamus (Thal), nociceptive information reaches the neurons in the ACC from the spinal cord dorsal horn. These information affect neural activities of deeper cingulate neurons by direct thalamic projecting or intercortical inputs from layer II and III cells. Many of deep cingulate neurons then send their direct projections to the spinal cord, and possibly affect spinal pain transmission. B, Detailed cortical circuits within the ACC. Pyramidal cells in layer II/III form direct synaptic connections with neurons in layer V/VI within the ACC. Enhanced synaptic transmission from Layer II/III to V is likely to activate or enhance descending facilitatory modulation from the ACC to the spinal cord. C, A synaptic model shows postsynaptic potentiation of excitatory transmission in layer V cells after peripheral nerve injury. PKA-dependent AMPARs GluR1/3 subtypes insertion is likely a key cellular mechanism for this postsynaptic potentiation.