Some types of nerve pain persist long after the initial injury heals, yet this pain experience appears to serve no evolutionary purpose. Pain persistence may involve abnormal activity in the PFC, which can increase or decrease peripheral pain signals at the level of the dorsal horn by modulating neurotransmission in the periaqueductal gray region. Using an animal model of neuropathic pain, the spared nerve injury (SNI) model, in transgenic GFP-Fos rats, we identified an evolving, pain-related hyperactivity in a subpopulation of Fos positive PFC neurons. Enhancing Kv7 channel inhibition in these neurons reversed the hyperactivity and blocked the peripheral pain associated with SNI. In collaboration with the Largent-Milnes and Vanderah laboratories, we found that disrupting local neurotransmission in the downstream PAG prevented the pain-relieving action of the Kv7 channel stabilizer in the PFC, indicating ongoing increased transmission from the PFC to the PAG exacerbates the perception of pain.  As a part of the Comprehensive Pain and Addiction Center (CPAC), our lab is investigating the importance of these PFC changes in two ways. First, we are evaluating CaMKII, as a regulator of PFC activity and bradykinin-mediated hyperactivity. Second, because the same brain region (PFC) and mechanisms (inhibitory Kv7 channels) appear to regulate both pain perception and cue-induced (relapse-like drug-seeking) behavior, we are examining if synergistic cellular actions of may mediate the addictive aspects of pain-relieving opiates.