Figure 1.

Central and somal signals received by nociceptors during SCI, and consequences of switching nociceptors into a persistent hyperfunctional state. Nociceptors receive injury-related signals within the spinal cord (from intensely activated postsynaptic dorsal horn neurons [DH], activated glia, and infiltrating immune cells) and within the DRG (from other DRG neurons, satellite glial cells, and the blood). Nociceptors have potent excitatory effects on pain pathways (indicated by DH neurons) and on circuits subserving somatic and visceral functions (not shown). LTP at DH synapses can be produced by somal and peripheral SA and afterdischarge, facilitated by the nociceptor hyperfunctional state (including the somal hyperexcitable/SA [HSA] state). Nociceptor activity produces central sensitization, promotes spontaneous and evoked pain, and enhances somatic and visceral reflexes. Nociceptor activity also leads to positive feedback interactions with postsynaptic neurons, other DRG somata, inflammatory cells (microglia, infiltrating macrophages, and T cells), astrocytes, and satellite glial cells. Similar interactions of peripheral branches with surrounding cells are possible, but are less likely after central than peripheral injury and are not indicated here. Because SCI severs or demyelinates many ascending fibers, much of the activity in pain pathways generated below the injury level may be blocked, although residual pathways (illustrated) are likely to contribute to the sensation of below-level pain in cases of incomplete SCI. Conversely, interruption of descending inhibitory pathways enhances spinal excitability, promoting entry of nociceptors into the hyperfunctional state and further increasing the somatic and autonomic hyperreflexia and visceral dysfunction driven by SA in below-level nociceptors. Nociceptor SA generated immediately above the injury level should have ready access to intact spinal circuits and projection neurons in pain pathways, contributing to central sensitization, behavioral hypersensitivity, and at-level pain. At-level nociceptor alterations may involve additional signals generated by direct damage to the nociceptor (axotomy) and to nearby cells.