THE DARK SIDE OF CEREBELLUM IN OPIOID USE DISORDER VULNERABILITY

Early life stress (ELS) is considered a key contributor to increased vulnerability to substance abuse disorders. Maternal separation (MS), a widely used mouse model of ELS, has been shown to enhance morphine sensitivity and alter opioid signaling within brain regions involved in reward and emotional regulation. Although the cerebellum is the brain region with a highest density of μ-opioid receptors (MOR), little is known about the functional role of the cerebellar opioid signaling at the cellular level, particularly in the context of ELS. Here we investigated the impact of MS on opioid responsiveness and MOR expression in the cerebellum, using electrophysiological and molecular approaches. CD1 pups underwent MS from postnatal day P2 to P18 for 4 h/day. Patch- clamp recordings, immunofluorescence, and western blot analysis were performed on cerebellar samples of MS and control mice at P20. In control mice, the MOR agonist DAMGO significantly reduced synaptic transmission at the parallel fiber–Purkinje cell synapse, whereas this effect was absent in MS mice. In contrast, both groups showed comparable responses to the κ‑opioid receptor agonist U50488. Wester blot analyses revealed decreased levels of phosphorylated MOR in the cerebellar cortex of MS mice respect to controls. Together, these findings indicates that MS disrupts MOR-mediated neuromodulation of Purkinje cells. Such alterations may impair cerebellar processing and could contribute to motor disturbances, such as tremor and ataxia, observed in individuals with chronic opioid exposure or opioid abuse.