Loss of Sfrp2 contributes to the neurological disorders related with morphine withdrawal via Wnt/β-catenin signaling

Morphine administration is a medical problem characterized by compulsive opioid use that causes terrible negative consequences. The exact mechanisms of morphine-induced dependence and morphine withdrawal symptoms remain unclear. Recent studies have revealed that the upregulation of Wnt/β-catenin signaling plays important roles in morphine exposure and morphine withdrawal. Secreted frizzled-related protein 2 (Sfrp2) can prevent the activation of Wnt/β-catenin signaling by competing with the Frizzled receptor for Wnt ligands. We conducted this study aimed to evaluate the effect of iatrogenic trauma induced by stereotactic surgery and the protective effect of stereotaxic Sfrp2 injection on morphine withdrawal symptoms in Male Sprague Dawley (SD) rats. Many techniques including western blot analysis and immunoprecipitation were used. Anxiety-related behaviors, morphine withdrawal syndrome, and dendritic spines were also examined in male SD rats after morphine treatment and stereotaxic injection of Sfrp2. Western blot results suggested that Wnt signaling was activated in the nucleus accumbens of SD rats suffering from morphine withdrawal and that Sfrp2 attenuated the overexpression of Wnt signaling. Similarly, the withdrawal-like symptoms of morphine dependent rats were abrogated by intracerebral Sfrp2 injection. The iatrogenic trauma induced by stereotactic surgery showed no influence on the Wnt signaling and withdrawal-like symptoms. Moreover, the results of Golgi-cox staining and DiI staining indicated that the damage on proximal spine density caused by morphine treatment was restored by intracerebral Sfrp2 injection. Together, the data presented here indicated that Sfrp2 abrogated the neurological disorders and loss of proximal spine related with morphine withdrawal via Wnt/β-catenin signaling.