Spinal PKCs solely contribute to the initial induction of persistent pain, whereas PKMζ plays an essential role in spinal plasticity storage. PKMζ is responsible for the maintenance of peripheral inflammation-primed PPSP. Therefore, spinal PKMζ may be a therapeutic target to prevent surgery-induced chronic pain in patients with preoperative pain.

The use of human telomerase reverse transcriptase-immortalized bone marrow mesenchymal stromal cells (hTERT-BMSCs) as vehicles to deliver antinociceptive galanin (GAL) molecules into pain-processing centers represents a novel cell therapy strategy for pain management. Here, an hTERT-BMSCs/Tet-on/GAL cell line was constructed using a single Tet-on-inducible lentivirus system, and subsequent experiments demonstrated that the secretion of rat GAL from hTERT-BMSCs/Tet-on/GAL was switched on and off under the control of an inducer in a dose-dependent manner. The construction of this cell line is the first promising step in the regulation of GAL secretion from hTERT-immortalized BMSCs, and the potential application of this system may provide a stem cell-based research platform for pain.

Management of chronic pain is one of the most difficult problems in modern practice. Grafted human telomerase reverse transcriptase–immortalized bone marrow mesenchymal stromal cells (hTERT-BMSCs) with inducible galanin (GAL) expression have been considered to be a potentially safe and controllable approach for the alleviation of chronic pain. Therefore, in this study, we aimed to assess the feasibility of hTERT-BMSCs/Tet-on/GAL cells secreting GAL under the transcriptional control of doxycycline (Dox) for controllable pain relief. After transplanted into the subarachnoid space of neuropathic rats induced by spared nerve injury of sciatic nerve, their analgesic actions were investigated by behavioral tests. The results showed that the pain-related behaviors, mechanical allodynia, and thermal hyperalgesia were significantly alleviated during 1 to 7 weeks after grafts of hTERT-BMSCs/Tet-on/GAL cells without motor incoordination. Importantly, these effects could be reversed by GAL receptor antagonist M35 and regulated by Dox induction as compared with control. Moreover, the GAL level in cerebrospinal fluid and spinal GAL receptor 1 (GalR1) expression were correlated with Dox administration, but not GAL receptor 2 (GalR2). Meanwhile, spinal protein kinase Mζ (PKMζ) expression was also inhibited significantly. Taken together, these data suggest that inducible release of GAL from transplanted cells was able to produce controllable pain relief in neuropathic rats via inhibiting the PKMζ activation and activating its GalR1 rather than GalR2. This provides a promising step toward a novel stem cell–based strategy for pain therapy.