Spontaneous oxycodone withdrawal alters behavior and oligodendrocyte-related gene expression in mice

Negative affective signs are induced during withdrawal from acute opioid injection and increase in magnitude over repeated injections. Recent evidence indicates that opioid use also causes alterations in oligodendrocyte differentiation and myelination. To investigate these phenomena in mice, we examined spontaneous withdrawal following 10 days of oxycodone administration (30 mg/kg/day). Following a single injection, oxycodone increased exploratory locomotion and elevated thermal pain thresholds, consistent with the acute effect of opioid drugs. Twenty-four hours after oxycodone injection, mice interacted less in an open field, but did not differ from controls in the three-chamber social preference task. The following day (i.e., at the 48-h withdrawal point), oxycodone-withdrawn animals showed decreased marble burying. Tissue harvested from the medial prefrontal cortex (mPFC) after this test was analyzed for expression for 5 genes associated with regulation of oligodendrocyte cell lineage progression. RT-qPCR revealed decreased expression of Tcf7l2 and Klk6. These findings indicate behavioral and neurobiological alterations in response to oxycodone. The increased locomotion and antinociception seen following an acute oxycodone dose corroborates past rodent studies. Decreased marble burying during withdrawal represents a novel finding and may reflect anhedonia. The observed changes suggest that alterations in myelin-related gene expression accompany affective signs of acute withdrawal after repeated opioid exposure.