Morphine withdrawal modifies PrP expression in rat hippocampus

Aims. Prion protein (PrPC), like many GPI-anchored protein, is found in sphingolipid-rich membrane microdomains known as lipid raft. This membrane-bound isoform dimerizes and can act as cell surface receptor, co-receptor or form multimolecular complexes and recruit downstream signal transduction pathways. As known, dimerization of membrane-bound PrPC leads to clustering in multimolecular complexes and serves to regulate different aspect of neuronal homeostasis, while intracellular dimerization appears to be the most relevant event in neuroprotection, via N1 and C1 prion metabolites. Repeated exposure to opioids may alter the brain so that it functions normally when the drugs are present, thus, a prolonged withdrawal might lead to homeostatic changes headed for restoration of physiological state. During morphine withdrawal, stress responses might be responsible, at least in part, for long-term changes of hippocampal plasticity and affect metaplasticity. We hypothesize that stressful stimuli induced by opiate withdrawal, and the subsequent long-term homeostatic changes in hippocampal plasticity, might modulate the expression of PrPC. Methods. Male Sprague–Dawley rats were treated with morphine hydrochloride twice daily for 14 days and divided in seven groups with different withdrawals. Homogenized hippocampi and prefrontal cortices were subjected to western blot analisys with different PrP antibodies. We evaluated the generation of PrPC oligomeric species, such as dimers, which could further aggregate into resistant form of PrP. Results. Although neither acute, nor chronic morphine exposure, influenced PrPC expression in hippocampus or prefrontal cortex, abstinence from opiate induced a time-dependent and region-specific modification in PrPC content. In fact, one week after morphine withdrawal, PrPC expression in the hippocampus, but not in the prefrontal cortex, was significantly increased, and this effect was still present 14 days after last morphine exposure. This PrPC overexpression in hippocampal tissue may be linked to generation of PrPC dimeric structure moreover opiate withdrawal led to α-cleavage at the PrPC hydrophobic domain and consequent PrPN1/C1 fragments production. Conclusions. We speculate that this might be the mechanism by which stressful stimuli induced by opiate withdrawal and the subsequent long-term homeostatic changes in hippocampal plasticity, modulate the expression and the dynamics of PrPC. We show the aggregation of PrPC in a biological process not related to neurodegeneration. Our results may suggest that PrPC dimerization, and its further aggregation in partially resistant oligomers, may play a role in the restoration of network homeostasis associated with withdrawal from morphine.