away are severed by spinal cord injury, too far for the calcium to diffuse (Hains et al., 2003a). Therefore, besides calcium influx, there are likely other triggers of apoptosis in spinal cord injury.
The chronic phase of spinal cord injury sets in over a period of months to years. The chronic phase is marked by the emergence of new types of pathology at both the microlevel and the macrolevel (e.g., the formation of a fluid-filled cavity or a glial scar). At the microlevel, the death of oligodendrocytes has an amplifying effect. Because most oligodendrocytes myelinate (i.e., insulate) about 10 to 40 nerve axons, the loss of one oligodendrocyte can leave many healthy nerve axons without conduction capacity. If nerve conduction is stopped entirely, the spinal cord cannot transmit signals to the brain and body, even though axons may be intact. Axons undergo molecular changes, such as alteration of the ion channels that are normally responsible for propagating electrical impulses through nerves (Waxman, 2001; Hains et al., 2003b). The combination of myelin loss and altered ion channel function, among other changes, can lead to molecular changes in the surviving neurons that can produce chronic pain in animals with experimental spinal cord injuries. At the macrolevel, the lesion site becomes increasingly devoid of normal tissue and begins to form a fluid-filled cavity or a glial scar, or both. The cavity forms within a few weeks of injury in animal models and may extend several segments above and below the site of injury. The cavity creates a physical gap that blocks axon regrowth, whereas the glial scar contains substances that inhibit axon regrowth.
Glial scarring (also known as reactive gliosis) creates an environment that inhibits axon regeneration. The glial scar is an extracellular matrix that contains astroyctes, microglia, and oligodendrocytes. It grows in size over time, from weeks to months after the injury, but the groundwork is set within hours of the injury. That is when the remnants of the acute phase—myelin debris and damaged axons—begin to accumulate at the site of the injury. The remnants begin to attract an array of different types of glial cells, from oligodendrocytes and their precursors to activated microglia and astrocytes. Astrocytes are most commonly found in the scar, and they are tightly bound to one another (Fawcett and Asher, 1999). If the spinal cord has been penetrated, meningeal cells, which normally form a protective layer around the spinal cord, also accumulate at the lesion site. Each type of cell expresses and/or releases a host of inhibitory molecules (Table 2-6).