Abstract
The knowledge about proteome changes proceeding during protracted opioid withdrawal is lacking. Therefore, the aim of this work was to analyze the spectrum of altered proteins in the rat hippocampus in comparison with the forebrain cortex after 6-month morphine withdrawal. We utilized 2D electrophoretic workflow (Pro-Q® Diamond staining and Colloidal Coomassie Blue staining) which was preceded by label-free quantification (MaxLFQ). The phosphoproteomic analysis revealed six significantly altered hippocampal (Calm1, Ywhaz, Tuba1b, Stip1, Pgk1, and Aldoa) and three cortical proteins (Tubb2a, Tuba1a, and Actb). The impact of 6-month morphine withdrawal on the changes in the proteomic profiles was higher in the hippocampus—14 proteins, only three proteins were detected in the forebrain cortex. Gene Ontology (GO) enrichment analysis of differentially expressed hippocampal proteins revealed the most enriched terms related to metabolic changes, cytoskeleton organization and response to oxidative stress. There is increasing evidence that energy metabolism plays an important role in opioid addiction. However, the way how morphine treatment and withdrawal alter energy metabolism is not fully understood. Our results indicate that the rat hippocampus is more susceptible to changes in proteome and phosphoproteome profiles induced by 6-month morphine withdrawal than is the forebrain cortex.
Highlights
Morphine is still considered a frequently used opioid in the treatment of moderate to severe pain
We extended the withdrawal period from 3 to 6 months and applied gel-based proteomics to analyze the alterations in both protein expression and protein phosphorylation in the rat hippocampus and forebrain cortex
Our results suggest that protracted morphine withdrawal causes significant proteomic changes in the energy metabolism of different rat brain parts
Summary
Morphine is still considered a frequently used opioid in the treatment of moderate to severe pain. The analgesic effect is caused by the activation of the opioid receptors (ORs). Bourova et al [5] described that exposure of rats to increasing doses of morphine (10–50 mg/kg, 10 days) results in significant desensitization of μ-OR- and δ-OR-stimulated G protein response in the rat forebrain cortex. These findings were in agreement with the data published previously [6,7,8,9,10,11]. The same applied to Na, K-ATPase, and caveolin-1 [12,13]
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