PROJECT SUMMARY The goal of this work is to identify pain-induced adaptations in the prefrontal cortical dynorphin / kappa-opioid receptor system and the role this system plays in pain-induced mal-adaptive behavior and nociception. Chronic pain drives adaptations in prefrontal cortical circuits and is hypothesized to increase bias towards aversive experiences. Our preliminary data demonstrates that inhibitory and excitatory populations of prefrontal cortical dynorphin neurons are activated and release dynorphin neuropeptide in response to aversive stimuli. However, it is unclear whether prefrontal cortical dynorphin neuron activity and ensuing dynorphin release is impacted by pain. To address this knowledge gap, we will perform ex-vivo electrophysiological procedures and in-vivo single cell calcium imaging in freely moving mice to determine how pain influences activity of excitatory and inhibitory prefrontal cortical dynorphin neurons and their responsivity to noxious stimuli and aversive stimuli. Moreover, we will manipulate the activity of prefrontal cortical dynorphin neurons and release of dynorphin neuropeptides or fast transmitters to determine whether enhanced prefrontal cortical dynorphin neuron activity and transmitter release controls nociception and mal-adaptive affective behavior induced by pain. Taken together, this work will identify how genetically-defined sub-populations of prefrontal cortical neurons and the opioid peptides or fast excitatory and inhibitory transmitters they release influence negative affect induced by pain from the cellular to in-vivo level of analysis. This work is of broad relevance as it elucidates basic principles by which neuropeptide- expressing neurons in prefrontal cortical circuits control behavioral plasticity and delineate potentially new therapeutic targets for the treatment of mal-adaptive affect and increased responsivity to noxious and aversive stimuli associated with pain states.

PROJECT NARRATIVE To date, science has not produced a detailed elucidation of the circuitry involved in the physiological and emotional response to pain. The goal of this project is to identify the neural mechanisms through which surgical and neuropathic pain alters circuit function dynorphin-expressing neurons in the medial prefrontal cortex (mPFC). Because the mPFC is a key node in the emotional network of the brain, findings from this project should produce critical knowledge regarding the affective dimension of pain and pain disorders that could lead to novel strategies for analgesic therapies.