An Engineered Endomorphin-2 Gene for Morphine Withdrawal Syndrome

Abstract

An optimal therapeutics to manage opioid withdrawal syndrome is desired for opioid addiction treatment. Down-regulation of endogenous endomorphin-2 (EM2) level in the central nervous system after continuous morphine exposure was observed, which suggested that increase of EM2 could be an alternative novel method for opioid dependence. As a short peptide, the short half-life of EM2 limits its clinical usage through conventional administration. In the present study, we engineered an EM2 gene using a signal peptide of mouse growth factor for an out-secretory expression of EM2 and an adenovirus as a vector, which ultimately sustained the release of EM-2. After administration of the adenovirus in central nervous system, a sustained increase of EM2 level in the cerebral spinal fluid (CSF) was observed along with a reduction of morphine withdrawal syndrome. These findings suggest that the engineered EM2 gene delivered to the central nervous system could be a novel therapeutics for withdrawal syndrome in opioid dependent subjects.

Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics

“…Therefore, the discovery of novel peptides based on the structure of the EMs with a high efficiency and extremely attenuated undesired effects has become a hotspot in the field of medicine [46][47][48][49][50][51]. Substantial attempts have been made to study their structureactivity relationships, and modifications, such as methylation, glycosylation and lipidation, etc., directed at these sites have achieved promising results [46][47][48][49][50][51][52]. Here, we selectively report some of the important modifications of EMs (Table 3).…”

“…Moreover, the reduced withdrawal syndrome in an opioid dependent rat model was observed after administrating the engineered EM2 gene into the CNS, opening another potential application of EMs in the management of withdrawal syndrome in opioid dependent subjects [52].…”

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

“…The biological characteristic of β-EP in specific brain regions, such as the lateral cerebral ventricle and nucleus arcuatus hypothalamus, has been confirmed to be involved in the addiction process. 17 Wu et al 40 found that reversal of acute morphine withdrawal syndrome behaviors contributed to a sustainable increase in endomorphin-2 in the CSF by intrathecal injection of an adenovirus engineered to express the endomorphin-2 gene. These results supported the hypothesis that opioid addiction and relapse could be improved by external secretion of the endogenous opioid peptide in targeted brain regions via CSF circulation.…”