Investigation of the endogenous opioid neural circuitry in pain

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PROJECT SUMMARY The opioid epidemic has encouraged the biomedical research community to explore new pain targets and further study opioid’s most famous target, the mu opioid receptor. One underexplored arena is the study of the endogenous opioid peptide system, which we know very little especially in comparison to our knowledge of the receptors they activate. This is despite the commonsense understanding that the endogenous peptides must change as a result of the allostatic load imposed by chronic pain, opioids, and chronic opioid exposure. There are well established sex differences in the actions of opioids at the mu opioid receptor, but it is unknown whether there are also differences in the endogenous opioid peptides. The experiments outlined here lay the necessary and long overdue groundwork to understand the neural mechanisms of one class of the endogenous opioids, called enkephalins, and how they contribute to pain. In the first aim, we will quantify enkephalin mRNA expression in regions of the brain known to play a role in top-down pain modulation. Next, we will use a viral retrograde tracer to map the enkephalin containing neurons that synapse in the PAG, something that has never been done before. In Aim 2 we will probe the behavioral effects of activating enkephalin containing neurons that synapse in the PAG using excitatory and inhibitory chemogenetic approaches followed by assessment on pain assays. We expect that increasing activation of all enkephalin neurons that synapse in the PAG will result in increased antinociception. Further, we expect that inhibition will lower the endogenous opioid release and therefore produce pain. We will further isolate certain neural projections from one brain region at a time to elucidate which brain regions are driving the enkephalin mediated antinociceptive responses. This research will allow us to better understand how the endogenous opioid system facilitates pain control and whether there are underlying differences that lead to differences in pain modulation in males and females.