Neuroinflammation and Central Sensitization in Chronic and Widespread Pain

Ru-Rong Ji, Ph.D.; Andrea Nackley, Ph.D.; Yul Huh, B.S., M.S.; Niccolò Terrando, Ph.D.; William Maixner, D.D.S., Ph.D.


Anesthesiology. 2018;129(2):343-366. 

In This Article

Long-term Potentiation, Central Sensitization, and Widespread Pain

Spinal cord long-term potentiation is an important form of synaptic plasticity and a unique form of central sensitization in chronic pain.[222,223] Spinal cord long-term potentiation of C-fiber–evoked field potentials is typically induced by high-frequency tetanic stimulation of the sciatic nerve.[224] Spinal cord long-term potentiation is also induced by nerve injury and opioid withdrawal.[225–227] There are striking similarities between spinal cord long-term potentiation and central sensitization, and both show the critical requirements of NMDA receptor and involvement of key signaling transduction pathways including the protein kinase C, extracellular signal-regulated kinase, and Src, as well as dependence of protein synthesis and gene transcription.[38,179,228] However, maintenance of late-phase long-term potentiation (greater than 4 h) may require additional mechanisms.[225] It remains to be determined whether there is persistent spinal long-term potentiation months after painful insults, due to technical difficulty in following long-term potentiation over time.

Several lines of evidence suggest an essential role of neuroinflammation in inducing and sustaining spinal cord long-term potentiation. First, spinal tumor necrosis factor is both sufficient and required for the induction of spinal cord long-term potentiation via both tumor necrosis factor receptors type I and type II.[202,229] Caspase-6 also contributes to the induction and maintenance of spinal cord long-term potentiation via tumor necrosis factor signaling.[166] Second, interleukin-1β triggers spinal cord long-term potentiation not only in excitatory synapses[230] but also in glycinergic synapses on GABAergic neurons in spinal cord slices,[231] serving as another example of cytokine-induced disinhibition. Third, activation of spinal microglial CX3C chemokine receptor 1 via chemokine CX3C ligand 1/fractalkine is sufficient to elicit spinal cord long-term potentiation.[232] Finally, chemokine (CC motif) receptor 2 is required for the maintenance of spinal cord long-term potentiation.[214]

Recently, Kronschläger et al.[233] demonstrated a gliogenic spinal cord long-term potentiation that can spread widely in nociceptive pathways. A fundamental feature of long-term potentiation induction in the brain is the requirement for coincident pre- and postsynaptic activity, which is important to restrict long-term potentiation expression to activated synapses only (homosynaptic long-term potentiation) as well as to define the input specificity of long-term potentiation. Gliogenic spinal cord long-term potentiation can travel long distances via cerebrospinal fluid, because this long-term potentiation can be induced by glial activation and diffusible messengers, such as D-serine and tumor necrosis factor.[233] Strikingly, transfer of spinal cerebrospinal fluid from a donor animal displaying long-term potentiation is able to induce long-term potentiation in a naïve receiver animal.[233] Therefore, this diffusible spinal cord long-term potentiation affects susceptible synapses at remote sites. Collectively, gliogenic long-term potentiation, as well as other forms of diffusible and glial-mediated central sensitization, may underlie widespread pain in chronic pain patients, especially in those with overlapping chronic pain conditions (Figure 6).

Figure 6.

Nonpharmacologic approaches that can control neuroinflammation and produce multiple beneficial effects including prevention and resolution of chronic pain, prevention of neurodegeneration, and repair of cognitive function deficits. DHA = docosahexaenoic acid; DRG = dorsal root ganglia; EA = electroacupuncture; EPA = eicosapentaenoic acid; SPM = specialized proresolution mediator; TENS = transcutaneous electrical nerve stimulation; TMS = transcranial magnetic stimulation.

Synaptic plasticity and long-term potentiation have also been investigated in the brain, such as in the anterior cingulate cortex,[234] amygdala,[235] and hippocampus[236] after tissue and nerve injury. Further investigation is warranted to define the role of neuroinflammation and glial activation in these pain-associated synaptic changes in the brain.