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.

Disclosures

Anesthesiology. 2018;129(2):343-366. 

In This Article

Neuroinflammation Drives Central Sensitization and Widespread Pain via Glia-produced Cytokines and Chemokines

An important step forward in revealing the role of central sensitization in widespread chronic pain is to demonstrate direct involvement of cytokines and chemokines (small cytokines) in the induction and maintenance of central sensitization.[150,193–195] In 2001, Samad et al.[193] showed that spinal interleukin-1β contributes to central sensitization and inflammatory pain hypersensitivity via transcriptional regulation that causes upregulations of cyclooxygenase-2 and prostaglandin E2. Notably, unilateral inflammation in the hind paw of rats caused widespread and bilateral increase of cyclooxygenase-2 in the spinal cord and brain, due to possible increase of interleukin-1β level in the cerebrospinal fluid.[193] This may partially explain widespread pain in some chronic pain conditions (Figure 4). However, contribution of the spinal cyclooxygenase/prostaglandin E2 pathway to central sensitization is not supported by a clinical trial in postoperative pain.[196] Despite a critical contribution of prostaglandin E2 to peripheral sensitization, the involvement of this important inflammatory mediator in regulating central sensitization is not well studied, but see the work of Ahmadi et al.[197] In 2008, Kawasaki et al.[194] demonstrated a direct induction of central sensitization by the proinflammatory cytokines tumor necrosis factor, interleukin-1β, and interleukin-6. These cytokines elicit very rapid increases (within 1 min) in excitatory synaptic transmission on spinal cord neurons. In support of this direct modulation, tumor necrosis factor, interleukin-1β, and interleukin-6 rapidly modulate the function of neurotransmitter receptors such as AMPA receptor, NMDA receptor, glycine receptor, and GABAR, which results in enhanced excitatory synaptic transmission and suppressed inhibitory synaptic transmission in the spinal pain circuit.[194] In agreement with this finding, intrathecal injection of tumor necrosis factor, interleukin-1β, or interleukin-6 elicits rapid pain hypersensitivity in naive animals.[194] Because these cytokines are elevated and circulating cerebrospinal fluid in chronic pain conditions,[198,199] they are possible mediators of widespread pain, as a result of widespread central sensitization (Figure 4).

Tumor necrosis factor can be produced by microglia, astrocytes, and even dorsal root ganglia primary sensory neurons.[200,201] However, in the spinal cord, tumor necrosis factor is primarily produced by microglia, as indicated by single-cell analysis of microglia, astrocytes, and neurons.[166] Electrophysiologic analysis reveals that tumor necrosis factor increases glutamate release in transient receptor potential ion channel V1+ C-fiber terminals, leading to enhanced excitatory synaptic transmission in lamina IIo excitatory spinal cord dorsal horn interneurons.[202] These lamina IIo interneurons synapse to lamina I projection neurons to form a pain circuit and potentiate pathologic pain.[84] Tumor necrosis factor also increases NMDA currents in IIo excitatory interneurons via extracellular signal-regulated kinase activation.[187] Additionally, tumor necrosis factor inhibits spontaneous action potentials in GABAergic neurons in the dorsal horn.[203] Both type I and type II receptors of tumor necrosis factor are involved in behavioral manifestations of central sensitization after intrathecal tumor necrosis factor treatment or during formalin-induced second-phase pain.[204] Notably, caspase-6 triggers tumor necrosis factor release from microglia to elicit central sensitization via tumor necrosis factor receptor signaling.[166]

Interleukin-1β is expressed by both microglia and astrocytes in the spinal cord.[110,147,205] Interleukin-18, a highly related family member of interleukin-1β, is induced in microglia by nerve injury and bone cancer.[133,206] Caspase-1 cleaves and activates interleukin-1β and interleukin-18 and acts as a key component of inflammasome, which contributes to the pathogenesis of chronic pain.[207] In addition, matrix metalloproteases 9 and 2 have been implicated in interleukin-1β cleavage and activation and regulation of glial activation in early versus late phase of neuropathic pain.[208] Interleukin-1β induces central sensitization via both presynaptic modulation (increasing glutamate release)[194] and postsynaptic regulation (phosphorylation of NMDA receptor[209,210] and enhancement of NMDA current[194]). Endogenous interleukin-1β also potentiates presynaptic NMDA receptor function in neuropathic pain.[211] Furthermore, interleukin-1β suppresses inhibitory synaptic transmission and GABA and glycine-induced currents in spinal lamina IIo neurons.[194] Interleukin-18 also causes hyperactivity of spinal wide dynamic range neurons after mechanical stimuli in vivo.[133] Thus, cytokines regulate central sensitization through multiple mechanisms that involve presynaptic and postsynaptic modulation as well as excitatory and inhibitory synaptic transmission modulation.

Astrocyte-produced chemokines (CC motif) ligand 2 and chemokine (CXC motif) ligand 1 also play an important role in central sensitization and chronic pain.[139,150,212] Chemokine (CC motif) receptor 2, the major receptor for chemokine (CC motif) ligand 2 is expressed in neurons including dorsal root ganglia and spinal cord dorsal horn neurons.[150,213,214] Bath application of chemokine (CC motif) ligand 2 to spinal cord slices induces rapid extracellular signal-regulated kinase activation and causes extracellular signal-regulated kinase-dependent potentiation of NMDA currents in dorsal horn neurons via the activation of chemokine (CC motif) receptor 2 receptors.[150,214] Intrathecal injection of chemokine (CXC motif) ligand 1 induced extracellular signal-regulated kinase and cAMP response element–binding protein activation in spinal neurons via the stimulation of CXCR2 receptors,[212] which is epigenetically regulated after injury.[215] Notably, late-phase neuropathic pain and synaptic plasticity (excitatory postsynaptic current increase) in the spinal cord pain circuit, at 3 weeks after nerve injury, is transiently reversed by the CXCR2 antagonist SB225002. These results suggest an active role of chemokine (CXC motif) ligand 1/CXC motif chemokine receptor 2 in the maintenance of central sensitization.[139]

Glial cells also produce growth factors such as brain-derived growth factor and basic fibroblast growth factor to enhance central sensitization and chronic pain.[216,217] Brain-derived growth factor release from central terminals of primary afferents elicits central sensitization via activation of extracellular signal-regulated kinase and potentiation of NMDA receptor.[182,218–220] Brain-derived growth factor signaling in spinal microglia also facilitates central sensitization, neuropathic pain, and morphine tolerance.[216,221] Exposure of spinal lamina I projection neurons to brain-derived growth factor results in a depolarizing shift in the anion reversal potential, causing disinhibition of GABAergic system, a key regulatory mechanism in chronic pain.[216,221] Brain-derived growth factor also modulates excitatory synaptic transmission in spinal cord dorsal horn lamina I neurons via activation of protein kinase Fyn.[178]

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