The role of the nigrothalamic pathway in opioid-driven behaviors

点击翻译按钮获取中文摘要

Project Summary Chronic pain represents a significant clinical problem, affecting up to 20% of the general population. Over- prescription of opioid analgesics has led to the current opioid epidemic as these medications carry high abuse liability due to the rewarding effects they produce. Thus, to improve treatment strategies for pain and opioid dependence, it is necessary to uncover the neural mechanisms underlying these debilitating conditions. Opioid reward has traditionally been thought to involve disinhibition of midbrain dopamine neurons by local GABA interneurons. However, we recently found that GABA neurons with high expression of mu opioid receptors in the substantia nigra pars reticulata (SNr), a brain region largely ignored in the reward and addiction fields, play a critical role in heroin self-administration and relapse. Although SNr GABA neurons are known to form monosynaptic connections with neurons of the ventromedial thalamus (vmThal) and my preliminary data suggest that both regions play a critical role in opioid-driven behaviors, to date, there is no direct evidence of a causal role of the SNr->vmThal pathway in opioid self-administration, relapse and opioid-induced analgesia. To address this critical gap in our knowledge and uncover the novel circuitry underlying pain and opioid addiction, we will combine mouse self-administration with optogenetics and chemogenetic ablations to selectively manipulate the SNr->vmThal pathway. In Specific Aims 1 and 2 we will test the hypothesis that heroin self-administration and heroin-primed drug seeking in are mediated by inhibition of SNr GABA neurons projecting to the vmThal, causing disinhibition of postsynaptic glutamate neurons. In Specific Aim 3, we will determine whether the SNr->vmThal pathway plays a critical role in opioid-induced analgesia, by using optogenetic activation/inactivation or chemogenetic ablation of genetically defined neurons with caspase-3 neurotoxin in hot plate and tail flick assays. Given that woman have higher rates of prescription opioid use than men, we will investigate sex differences in heroin-driven behaviors. These experiments satisfy objectives of NIH Helping to End Addiction Long-term (HEAL) Initiative by linking addiction and pain-related neural substrates and identifying novel circuitry involved in both conditions from which millions of people suffer worldwide. Thus, the proposed research is clinically relevant, as uncovering the neurobiology of opioid addiction and nociception, will set the stage for improving treatment strategies that are desperately needed. Importantly, the proposed experiments are carefully designed with the thought of providing undergraduate students at Colgate University with the unique independent research experience involving cutting-edge techniques to enhance their scientific profile in preparation for careers in the biomedical field.