Axonal regeneration of sensory nerves is delayed by continuous intrathecal infusion of nerve growth factor

While it is well established that nerve growth factor is growth promoting for sensory neurons in culture, it is unclear whether it serves such a function in vivo. In fact, our previous studies led to the hypothesis that nerve growth factor could actually impair axonal regeneration by reducing the neuronal cell body response to injury. In the present study, the consequence of continuous intrathecal infusion of nerve growth factor on regeneration of sensory neurons was examined in rats given a bilateral sciatic nerve crush. Rats received nerve growth factor (125 ng/h) as a continuous infusion into the subarachnoid space of the lumbar spinal cord via an osmotic minipump (Alzet); controls received cytochrome C. At seven or 10 days, the pump was removed and L4 or L5 dorsal root ganglion exposed and injected with 50 microCi of (3H)leucine. Animals were killed 24 h later, the sciatic nerves removed, cut into 3 mm segments and the radioactivity in each segment determined by liquid scintillation spectrophotometry. Maximal regeneration distances (determined from the front of the resultant transport curves) were similarly reduced (by approximately 6 mm) in nerve growth factor-infused compared to cytochrome C-infused rats. Thus, regeneration rates (determined between eight and 11 days) were unaltered by nerve growth factor infusion; regeneration rates from cytochrome C-infused and nerve growth factor-infused animals were 2.8 mm/day and 3.1 mm/day, respectively. However, nerve growth factor significantly (P < 0.005) increased the delay to onset for regeneration by two days. Taken together, the present study demonstrates that nerve growth factor delays the onset of regeneration without affecting the rate of regeneration. The results implicate the involvement of at least two signals in the regulation of axonal regeneration in dorsal root ganglion neurons. It is suggested that the loss of nerve growth factor serves as an early, induction signal regulating the onset of regeneration and that a second, unidentified signal independently serves to maintain regeneration.