LUMBAR TRANSPLANTS OF IMMORTALIZED SEROTONERGIC NEURONS ALLEVIATE CHRONIC NEUROPATHIC PAIN

The RN46A cell line was derived from embryonic day 13 rat medullary ra phe cells by infection with a retrovirus encoding the temperature-sens itive mutant of SV40 large T antigen. This cell line is neuronally res tricted and constitutively differentiates following a shift to non-per missive temperature. Brain-derived neurotrophic factor (BDNF) induced the serotonergic phenotype and increased the survival of RN46A cells i n vitro. After transfection of the rat BDNF gene into RN46A cells, an autocrine BDNF-secreting cell line, 46A B14, was isolated and transpla nted into the rat CNS. Transplanted 46A-B14 cells had increased surviv al and enhanced serotonin (5HT) synthesis compared to 46A-V1 cells, RN 46A cells transfected with vector-alone. When 46A-B14 cells were trans planted in the lumbar subarachnoid space of the spinal cord 1 week aft er a chronic constriction injury (CCI) of the sciatic nerve, they surv ived longer than 6 weeks on the pia mater. Furthermore, the tactile an d cold allodynia and thermal hyperalgesia induced by CCI was significa ntly reduced during a 4-6- week period. The maximal effect occurred 1 week after transplantation. 46A-V1 cells, transplanted after CCI, did not survive beyond 2-3 weeks and had no effect on the allodynia and hy peralgesia induced by CCI. Acute intrathecal injection of the 5HT rece ptor antagonist methysergide decreased the antinociceptive effects sf the 46A-B14 cells to pre-transplant levels. These data suggest that a chronically applied, low local dose of serotonin near the dorsal horn was able to reverse the development of chronic neuropathic pain follow ing CCI. The use of neural cell lines that are able to deliver inhibit ory neurotransmitters such as serotonin, in a model of chronic pain of fers a novel approach to pain management. (C) 1997 International Assoc iation for the Study of Pain. Published by Elsevier Science B.V.