Attempted gene therapy for intractable pain: Dexamethasone-mediated exogenous control of beta-endorphin secretion in genetically modified cells and intrathecal transplantation

For optimal neural transplantation using gene engineering, it might be impo rtant to control the expression of the transfected gene extrinsically as re quired. This strategy could be very useful for the treatment of intractable pain that responds to opioids, For this purpose, we established a genetica lly modified embryonal carcinoma cell line (P19) in which the expression of beta -endorphin (beta -EP) could be controlled by the addition of dexameth asone. To obtain extrinsic control, we transfected the cells with pMAMneo c ontaining mouse MMTV-LTR as a promoter and cDNA of the artificial beta -EP. The upregulation of beta -EP, through the activation of MMTV by the admini stration of dexamethasone, was confirmed in vitro. Then we transplanted the se cells into the subarachonoid space in rats and evaluated the analgesic p otential of these cells in vivo by hot plate test and formalin test. In the rats that received beta -EP-producing cells, we observed prominent analges ic effects after the transplantation for a month. The administration of nal oxone blocked these effects. Intraperitoneal injection of 100 mg/kg dexamet hasone further enhanced these effects by up to two times. These data indica te obvious analgesic effects of the cells after the transplantation and the possible exogenous upregulation of transfected beta -EP gene expression in vivo. The application of this technique might provide a new therapeutic ap proach to various neurological diseases. (C) 2000 Academic Press.