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 important to control the expression of the transfected gene extrinsically as required. This strategy could be very useful for the treatment of intractable pain that responds to opioids. For this purpose, we established a genetically modified embryonal carcinoma cell line (P19) in which the expression of beta-endorphin (beta-EP) could be controlled by the addition of dexamethasone. To obtain extrinsic control, we transfected the cells with pMAMneo containing 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 administration of dexamethasone, was confirmed in vitro. Then we transplanted these cells into the subarachonoid space in rats and evaluated the analgesic potential of these cells in vivo by hot plate test and formalin test. In the rats that received beta-EP-producing cells, we observed prominent analgesic effects after the transplantation for a month. The administration of naloxone blocked these effects. Intraperitoneal injection of 100 mg/kg dexamethasone further enhanced these effects by up to two times. These data indicate 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 approach to various neurological diseases.
Ishii
K
K
Department of Neurosurgery, Oita Medical University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan.
Isono
M
M
Inoue
R
R
Hori
S
S
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D054278:Embryonal Carcinoma Stem Cells; D015316:Genetic Therapy; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D010147:Pain Measurement; D010148:Intractable Pain / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D012333:RNA, Messenger; D009270:Naloxone; D003907:Dexamethasone; D020932:Nerve Growth Factor