Engineered endomorphin-2 gene: A novel therapy for improving morphine reinstatement in CPP model of rats by using deficient adenovirus as the vector

Abstract

Optimal therapeutics to deal with high relapse rates when discontinued is urgent for opioid dependence treatments. Endogenous endomorphin-2 (EM2) level in the central nervous system (CNS) down-regulates obviously after sustained morphine exposure, which suggested that to up-regulate the EM2 level could be a novel method for reinstatement. But the clinical applications of EM2 through conventional administration are limited owing to its short half-life. In our study, we engineered an EM2 gene to achieve the sustained release of EM-2 in CNS by utilizing a signal peptide of mouse growth factor for out-secreting EM2 and a deficient adenovirus as the vector. By intrathecally injecting engineering EM2 gene, a sustained increase of EM2 concentration in the cerebral spinal fluid (CSF) was observed along with a reduction of CPP scores. Also, the activation of astrocytes was suppressed in the hippocampus. In summary, this study provides evidence and reference for using intraspinal gene therapy with a combination of mouse growth factor and EM2 to treat morphine reinstatement.