Mechanisms of chronic central neuropathic pain after spinal cord injury

Abstract

Not all spinal contusions result in mechanical allodynia, in which non-noxious stimuli become noxious. The studies presented use the NYU impactor at 12.5 mm drop or the Infinite Horizons Impactor (150 kdyn, 1 s dwell) devices to model spinal cord injury (SCI). Both of these devices and injury parameters, if done correctly, will result in animals with above level (forelimb), at level (trunk) and below level (hindlimb) mechanical allodynia that model the changes in evoked somatosensation experienced by the majority of people with SCI. The sections are as follows: 1) Mechanisms of remote microglial activation and pain signaling in "below-level" central pain 2) Intracellular signaling mechanisms in central sensitization in "at-level" pain 3) Peripheral sensitization contributes to "above level" injury pain following spinal cord injury and 4) Role of reactive oxygen species in central sensitization in regional neuropathic pain following SCI. To summarize, differential regional mechanisms contribute to the regional chronic pain states. We propose the importance of understanding the mechanisms in the differential regional pain syndromes after SCI in the chronic condition. Targeting regional mechanisms will be of enormous benefit to the SCI population that suffer chronic pain, and will contribute to better treatment strategies for other chronic pain syndromes.

Figure 1

A massive release of glutamate at the SCI lesion epicenter triggers upregulation of the chemokine CCL21 both at the site of injury and in cell bodies of STT neurons whose axons have been exposed to high concentrations of glutamate. CCL21 is then released at remote sites from the injury activating microglia, thatcontributeto neuronal hyperexcitability in the spinal cord dorsal horn and thalamus. Abnormal amplification and generation of nociceptive signals at these levels contributes to chronic pain after injury.

Figure 2

SCI leads to persistent activation of intracellular signaling kinases such as ERK 1/2, p38 mitogen activated protein kinases (MAPK) and calcium calmodulin kinases (CaMKII) that lead to persistent activation of CREB, a transcription factor that contributes directly to factors that phosphorylated NR1 subunits of the NMDA channel, leading to persistent hyperexcitability of spinal and supraspinal neurons. This provides the substrate for persistent or neuropathic pain.

Figure 3

In the chronic SCI neuron, persistent activation of microglia and astrocytes contribute to production of proinflammatory cytokines, reactive oxygen species (ROS), ATP, excitatory amino acids, nitric oxide (NO) and other factors. Many of these factors, such as specific proinflammatory cytokines (ex. TNFα; IL-1α,β) trigger cytokine receptor mediated intracellular pathways in neurons that result in continued activation of NMDA, AMPA and metabotropic glutamate channels as well as cation channels. Thus, neuronal membranes remain hyperexcitable such that incoming sensory subthreshold input (ie. non-noxious stimuli) is now input into a “reset” circuit leading to altered sensory interpretations (ie. non-noxious stimuli becomes noxious: allodynia) or chronic pain.