Original Article

Gene Therapy (2017) 24, 314–324; doi:10.1038/gt.2017.22; published online 27 April 2017

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

T Iida1,3, H Yi1,3, S Liu1, D Ikegami1, W Zheng1, Q Liu1, K Takahashi1, Y Kashiwagi1, W F Goins2, J C Glorioso2 and S Hao1

  1. 1Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA
  2. 2Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

Correspondence: Dr S Hao, Department of Anesthesiology, University of Miami Miller School of Medicine, 1550 NW 10th Avenue, Miami, FL 33136, USA. E-mail: shao@med.miami.edu

3These authors contributed equally to this work.

Received 26 October 2016; Revised 11 February 2017; Accepted 13 March 2017
Accepted article preview online 3 April 2017; Advance online publication 27 April 2017



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.