Opioids, including endogenous opioids, enkephalin, dynorphin, and β-endorphin, differentially activate several classes of opioid receptors, including mu, delta, and kappa, encoded by OPRM1, OPRD1, and OPRK1, respectively. Previous efforts have mapped striatal expression of opioid receptors in non-human primates and rodents, characterizing species-specific and cell type-specific patterns of expression41,42. We investigated the expression of opioid receptors and cognate ligands within the dorsal striatum. First, OPRM1 was detected in each MSN subtype, with the highest level of expression in D1/D2-hybrid and D2-striosome MSNs (Fig. S5). We reproducibly detected OPRM1 in microglia across individuals and biological samples, consistent with findings in rodents32,43, establishing a potential pathway for opioids to directly modulate neuroimmune signaling5. D1-striosome MSNs expressed the gene encoding the preproprotein, prodynorphin (PDYN), while D2-matrix and D2-striosome MSNs co-expressed OPRD1 and proenkephalin (PENK) at markedly higher levels than other striatal cell types (Fig. S5). Preferential expression of OPRD1 and PENK in D2 MSNs in human striatum is consistent with rodent striatum44. Across MSNs, we detected OPRK1 expression at many folds lower than OPRM1, OPRD1, PENK, or PDYN, suggesting that targets of the
