Transgenic increase in the β‐endorphin concentration in cerebrospinal fluid alleviates morphine‐primed relapse behavior through the μ opioid receptor in rats

Abstract

Background Opioid‐primed relapse is a global burden. Although current strategies have improved, optimal therapy is urgently needed. Methods A recombinant adenovirus (Ad‐NEP) expressing β‐endorphin (β‐EP) was designed and injected intracerebroventricularly (icv) into the right lateral ventricle in rats. Spatial and temporal β‐EP expression in the lateral ventricle wall, subventricular zone and adjacent choroid plexus and the β‐EP concentration in the cerebrospinal fluid (CSF) were observed during a 21‐day period. A morphine priming‐induced conditioned place preference (CPP) rat model was established. The β‐EP‐ir neuron counts, CSF β‐EP concentration, and CPP score, which were used to evaluate morphine‐primed reinstatement following extinction, were recorded 7 days after the icv injection. Additionally, the rats were pretreated with the irreversible μ opioid receptor antagonist β‐funaltrexamine (β‐FNA) and the selective κ opioid receptor antagonist nor‐binaltorphimine (nor‐BNI) to identify the receptor‐dependent mechanism. Results Both peak β‐EP expression in target neurons and the peak CSF β‐EP concentration occurred 7 to 8 days after Ad‐NEP icv injection. The sustainable increase in the CSF β‐EP concentration was correlated with a decrease in the CPP score 7 days after the Ad‐NEP icv injection. Furthermore, reinstatement was almost reversed by β‐FNA pretreatment 24 hours before the behavioral test, but nor‐BNI had little effect. Conclusion The increasing cerebrospinal fluid β‐endorphin concentrations showed that the therapeutic effect on opioid relapse occurred predominantly through a μ opioid receptor‐dependent mechanism. The Ad‐NEP adenovirus can be considered an alternative therapy for opioid relapse.

A Runner’s High for New Neurons? Potential Role for Endorphins in Exercise Effects on Adult Neurogenesis

“…The opposite models, enhanced β-endorphin, would be helpful to show positive effects of running without the confounding additional physiological effects of exercise. Interestingly, an adenovirus has recently been created which chronically enhances β-endorphin levels centrally [131]. However, it is too soon to know whether this model can be used to imitate effects of running on behaviors related to the hippocampus and adult neurogenesis.…”