Project 462847

Chronic pain is a highly prevalent and debilitating condition afflicting one in five Canadians. Opioids, our current first line of defense against pain, are not viable strategies in treating chronic pain as they lose efficacy in the long term and commonly result in abuse disorders. The anterior cingulate cortex (ACC), a region of the prefrontal cortex processing the affective components of pain, is pathologically hyperactive in chronic pain. The ACC receives dense dopaminergic (DA) inputs from the midbrain and our data suggest DA can be an inhibitory neuromodulator in the ACC. Interestingly, hypodopaminergic pathologies such as Parkinson's disease (PD) and major depression, show a high prevalence of chronic pain. Working hypothesis: Dysregulation of DAergic signaling in ACC contributes to hyperexcitability of pyramidal neurons and defective top-down control of pain. Based on our expertise in electrophysiology and pain circuits, we propose to: Aim 1- To measure the effects of DA on GABAergic neurons in ACC We will investigate the neuromodulatory effects of DA on intrinsic excitability of classes of GABAergic interneurons in the mouse ACC using electrophysiology in brain slices. Aim 2- To monitor DAergic dysfunction in chronic pain We will measure the impact of neuropathic injury on cortical DA levels in the mouse model of chronic pain. Aim 3- To induce analgesia by rescuing defective DAergic inhibition in the ACC We plan to compensate for a potential deficit in DAergic function in the ACC in conditions of chronic pain using intersectional optogenetics on VTA neurons. Significance: The discovery of novel cortical mechanisms underlying abnormal pain perception can potentially lead to the testing of novel therapeutic strategies for effective non-opioid analgesia in chronic pain patients.