A Comprehensive Framework of Mu Opioid Receptor Mechanisms of Function in Anterior Cingulate and Somatosensory Cortex Neuron Types

While opioids are powerful analgesics, side effects including addiction and death through respiratory depression limit their clinical utility. Interrogating how opioids signal through distinct neuron types to either relieve pain or induce side effects may allow for development of more targeted pain medications. Although opioids bind the mu, kappa, and delta opioid receptors, the mu opioid receptor (MOR) is known to mediate both addictive and analgesic effects of clinically used and illicit opioid drugs, and we therefore focus on its distribution across neuronal circuits. Specifically, MORs are known to be expressed across the cerebral cortex, including in multiple areas involved in pain perception. To compare the effect of opioids across cortical regions mediating the sensory-discriminative and affective-motivational dimensions of pain, we resolved the MOR expression pattern in the primary somatosensory and anterior cingulate cortices using scRNAseq data from cortical samples prepared by SMART-seq technology. Using intersectional mouse genetic strategies based on marker genes derived from scRNA-seq data the spatial distribution, connectivity, and dynamic profiles of MOR-expressing subpopulations across cortical regions and layers were dissected using anatomical, viral tracing, and calcium imaging experiments. With specific focus on cell types conserved in humans, these experiments reveal the molecular architecture of opioid-sensitive cortical neurons and their contributions to opioid-induced behaviors. This work is supported by grants from the NIH (R01DA054583, G.S., H.K.Z., F30DA057839, N.E.O., F32DA057779, J.K.N), and the McKnight Endowment Fund for Neuroscience (G.S.).