Single-nuclei characterization of oxycodone's effects on dorsal peduncular nucleus

In addition to their intrinsic rewarding properties. opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a unique population of PBn-projecting pyramidal neurons restricted to the DPn that express μ-opioid receptors (μORs). Disrupting μOR signaling in these neurons switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify DPn neurons as key substrates for the abuse liability of opioids. 2 saline-injected (IP) samples, 2 oxycodone-injected (5mg/kg) samples