Sciatic nerve regeneration is not inhibited by anti-NGF antibody treatment in the adult rat.

Elevated nerve growth factor (NGF) is believed to play a role in many types of pain. An NGF-blocking antibody (muMab 911) has been shown to reduce pain and hyperalgesia in pain models, suggesting a novel therapeutic approach for pain management. Since NGF also plays important roles in peripheral nervous system development and sensory nerve outgrowth, we asked whether anti-NGF antibodies would adversely impact peripheral nerve regeneration. Adult rats underwent a unilateral sciatic nerve crush to transect axons and were subcutaneously dosed weekly for 8weeks with muMab 911 or vehicle beginning 1day prior to injury. Plasma levels of muMab 911 were assessed from blood samples and foot print analysis was used to assess functional recovery. At 8-weeks post-nerve injury, sciatic nerves were prepared for light and electron microscopy. In a separate group, Fluro-Gold was injected subcutaneously at the ankle prior to perfusion, and counts and sizes of retrogradely labeled and unlabeled dorsal root ganglion neurons were obtained. There was no difference in the time course of gait recovery in antibody-treated and vehicle-treated animals. The number of myelinated and nonmyelinated axons was the same in the muMab 911-treated crushed nerves and intact nerves, consistent with observed complete recovery. Treatment with muMab 911 did however result in a small decrease in average cell body size on both the intact and injured sides. These results indicate that muMab 911 did not impair functional recovery or nerve regeneration after nerve injury in adult rats.

Changes in neurotransmitter uptake in the spinal cord following peripheral nerve injury.

Changes in neurotransmitter systems of the spinal cord were studied in response to peripheral nerve injury. The uptake and compartmentalization of radiolabeled spinal cord neurotransmitters and transmitter precursors were examined as a function of time following unilateral sciatic nerve crush in adult mice. Accumulation of transmitter was measured within synaptosomally enriched fractions prepared using combinations of differential and density gradient centrifugations. The amount of transmitter substance recovered from these fractions was strongly dependent upon the amount of time following nerve injury and on the specific transmitter or precursor being examined (GABA, glutamate, glycine, and choline chloride). However, for each of these substances, uptake values returned to control levels within nine to twelve days after nerve crush. Localization of GABA changes postcrush revealed reciprocal differences between ipsilateral and contralateral sides of the spinal cord, as well as differences between segmental levels. Altered GABA uptake may reflect changes in the postcrush microchemical environment present during tissue processing, but may also be related to direct changes in the synaptic binding, transport, and compartmentalization of transmitter substance. The time course, magnitude, and direction of these neurochemical changes follow those observed neurophysiologically, and may thus underlie injury-induced short-term (days) alterations reported in primary afferent depolarizations, cross cord responses, and other spinal mechanisms.