The role of T-type calcium channels in the morphine effects in the nonspecific thalamus

PROJECT SUMMARY / ABSTRACT There is substantial interest in identifying intricate mechanisms of the morphine-mediated effects and opioid addiction in order to expand strategies for novel therapies. Although the role of nonspecific thalamus in regulation of consciousness is well documented, its possible role in the morphine-mediated effects and addiction is not well studied. Principal Investigator (PI) has recently discovered the role of CaV3.1 isoform of T-type calcium channels (T-channels) in the central medial nucleus of thalamus (CeM) in neuronal excitability regulation and thalamocortical oscillations during anesthesia. Furthermore, based on the new exciting preliminary data, the overarching goal of this proposal is to determine the functional role of CaV3.1 isoform of thalamic T-channels in the morphine effects and addiction. It is hoped that this may form foundation for novel approaches to treatment and/or prevention of opioid overuse. In Aim 1, I will use patch-clamp recordings and 2-photon calcium imaging from acute brain slices ex vivo and projection-specific targeting and manipulating CeM neurons to determine acute and lasting effects of morphine exposure (after repeated morphine exposure and morphine-induced conditioned place preference – CPP) on T-channels and excitability of CeM neurons. In Aim 2, I will use behavioral experiments relevant to the addiction: CPP and self-administartion (SA) models, in vivo viral silencing technologies (with small hairpin RNA (shRNA) and Cre-specific knocking-out (KO)) and chemogenetic method for transient behavioral modulation to investigate functional role of thalamic T-channels in addiction. Completion of these aims will generate new insights into the mechanisms of the morphine effects and opioid addiction that could identify new treatment options. The PI will receive mentorship and technical training in addictive behavior and viral technologies by experts in electrophysiology and viral technologies in motivated behaviors. University of Colorado and the Department of Anesthesiology provide exceptional facilities and resources for completing the proposed experiments, as well as having an exceptional reputation and record of accomplishment for mentoring and transitioning early-stage into independent investigators. The proposed training, education and research will provide the PI with the technical and professional training to become a successful, independent investigator.