MnSOD mediated by HSV vectors in the periaqueductal gray suppresses morphine withdrawal in rats

Abstract

Morphine appears to be the most active metabolite of heroin; therefore, the effects of morphine are important in understanding the ramifications of heroin abuse. Opioid physical dependence (withdrawal response) may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. However, the exact mechanisms of morphine withdrawal (MW) are not clear yet, and its treatment remains elusive. Periaqueductal gray (PAG) is one of the important sites in the pathogenesis of MW. Here, we used recombinant herpes simplex virus (HSV) vectors that encode the sod2 gene expressing manganese superoxide dismutase (MnSOD) to evaluate its therapeutic potential in MW. Microinjection of HSV vectors expressing MnSOD into the PAG reduced the MW syndrome. MnSOD vectors suppressed the upregulated mitochondrial superoxide, and endoplasmic reticulum stress markers (glucose-related protein 78 (GRP78) and activating transcription factor 6 alpha (ATF6α)) in the PAG induced by MW. Immunostaining showed that mitochondrial superoxide, GRP78 and ATF6α were colocalized with neuronal nuclei (a neuronal-specific marker), suggesting that they are located in the neurons in the PAG. These results suggest that overexpression of MnSOD by HSV vectors may relieve opioid dependence. This study may provide a novel therapeutic approach to morphine physical withdrawal response.

Morphine Addiction and Oxidative Stress: The Potential Effects of Thioredoxin-1

“…SOD-mimetic-agent-injection attenuated the effects of morphine on mitochondrial SOD activity (Motaghinejad et al, 2015b). MnSOD overexpressed by recombinant herpes simplex virus in the periaqueductal gray of morphine-withdrawn rats suppressed the upregulated mitochondrial superoxide and the activation of endoplasmic reticulum stress (Iida et al, 2017). Numerous studies have demonstrated that exogenous agents providing antioxidant activity could also inhibit the action of morphine.…”

Potential Therapeutic Applications of MnSODs and SOD‐Mimetics

“…[35] Gene therapy that involved ar ecombinant adeno-associated virus 2-mediated MnSOD, reduced acute skin injury greatly after administering as ingle dose of irradiation using 30 or 35 Gy. [40] Epperly et al,r eported that MnSOD plasmid liposomeg ene therapy reduced lipid peroxidationt hat is stimulated by radiation in the mouseo esophagus. [37] In vitro, adenoviral MnSOD aloned id not affect SCC-25 or HCPC-1 cell viability, but in combination with BCNU (a GPx andc atalase inhibitor) a synergistic increase in cell death was observed.…”

“…Such as tudy may provide an ew therapyt om orphine physicalwithdrawal response. [40] Epperly et al,r eported that MnSOD plasmid liposomeg ene therapy reduced lipid peroxidationt hat is stimulated by radiation in the mouseo esophagus. [41] In addition, intraorala dministration of SOD-plasmid/liposomes prevented mice from radiation-induced mucositis, while still exposing the orthotopically transplanted tumour to radiation damage.…”

“…Such results indicated that the over‐expression of MnSOD by HSV vectors may reduce opioid dependence. Such a study may provide a new therapy to morphine physical withdrawal response …”

Sirt3 mediated by lentiviral vector in the periaqueductal gray suppresses morphine withdrawal in rats: A preliminary study

“…Our unpublished data shows that MW increased the mitochondrial superoxide in the vlPAG and super-oxidative scavenger reduced MW behavioral response. We reported that herpes simplex viral vector over-expressing MnSOD in the vlPAG reduced MW behavioral response 69 . It is highly possible that Sirt3 mediated by the lentiviral vector suppressed MW behavioral response through activating MnSOD.…”