Chronic
neuropathic pain is a common symptom in clinical practice and patients with
chronic pain are subject to a greatly impaired quality of life. Grafted genetically-modified cells secreting
enkephalin have been considered an encouraging treatment for
chronic pain. Importantly, the transplanted cell as a therapeutic agent should be reproducible, safe, and controllable. In this study, by combining a
tetracycline-controlled (Tet-on) gene expression system and immortalized astrocytes, we attempted to engineer an immortalized astrocyte line carrying the human
preproenkephalin gene (
IASL/hPPE) under the transcriptional control of
doxycycline. These cells were then implanted into the subarachnoid space of chronic constrictive injury (CCI) rats and their
analgesic potential was investigated by behavioral tests. The results showed that the secretion of
enkephalin from
IASL/hPPE cells could be switched on and off under the regulation of
doxycycline in a dose-dependent manner. In addition, the mechanical and
thermal hyperalgesia induced by CCI was significantly alleviated during the 2-7 week period after grafts of
IASL/hPPE cells and the
analgesic effect could be regulated by
doxycycline. Moreover, spinal
enkephalin level could be modulated by the presence or absence of
doxycycline in
drinking water. Taken together, these data suggest that regulatable release of
enkephalin from transplanted cells near the spinal dorsal horn was able to reverse the development of chronic
neuropathic pain. Although improvements in the Tet-on system are necessary, this may provide an alternative approach for ex vivo
cell transplantation to treat
chronic pain.