Pain is a multidimensional experience that involves sensory, cognitive and affective factors that make the treatment of clinical pain challenging and often a financial burden. Mindfulness meditation has been shown to alleviate pain in experimental and clinical settings, and at the same time is cost-effective. However, the pain- relieving mechanisms of mindfulness meditation remain poorly characterized. The central research aim of the proposed K99/R00 application is to identify the behavioral, neural, and pharmacologic mechanisms associated with mindfulness-based pain relief. To accomplish this aim, Dr. Zeidan will employ a wide-ranging approach to disentangle the potential analgesic properties of mindfulness meditation. For one, meditation's palliative effects may simply reflect demand characteristics associated with the belief that one is meditating. To address this issue, Dr. Zeidan has developed and employed a sham mindfulness meditation intervention to test the hypothesis that mindfulness meditation activates higher-order brain regions [rostral anterior cingulate cortex (ACC)] to reduce pain when compared to sham mindfulness meditation. In contrast, sham meditation is postulated to reduce pain by activating brain regions associated with placebo-analgesia (dorsolateral prefrontal cortex) when compared to mindfulness meditation. Interestingly, meditation-related pain relief engages brain regions (ACC, anterior insula) containing a high concentration of opioid receptors. However, it is still unknown if meditation-related pain relief is mediated by endogenous opioidergic systems. Administration of an opioid antagonist during meditation and noxious heat stimulation is hypothesized to significantly reduce the pain- relieving effects of meditation. In addition, the specific neuro-functional connections associated with reducing pain by meditation remain unknown. Dr. Zeidan will employ neuroimaging and functional connectivity analyses to test the hypothesis that meditation will activate neural systems involved in cognitive reappraisal processes (ACC) to reduce pain-related brain activity. The knowledge to be gained from these research activities will provide novel mechanistic insight into the efficacy and analgesic properties associated with mindfulness meditation, an important consideration for the treatment of clinical pain. The training goal of this K99/R00 application is to gain additional experience in neuroimaging and pharmacologic methodologies to allow Dr. Zeidan to successfully transition to an independent career focused on identifying the specific analgesic properties of mindfulness meditation. The training plan includes individual and team-mentoring strategies, additional coursework in neuroscience, pharmacologic techniques, statistics, scientifically validated meditation training, and career development. Dr. Zeidan is strongly supported by his mentor and career development advisory committee that is composed of leading experts in their respective fields. The proposed training and research activities of this K99/R00 award will provide Dr. Zeidan with the resources, knowledge base and skills to establish an independent line of programmatic research on the mechanisms of mindfulness and pain.