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

Central Sensitization Controls Augmentation and Spread of Pain Hypersensitivity

Term Development

Central sensitization is a powerful phenomenon in the pain field. As a key mechanism of chronic pain, it also guides clinical treatment for conditions associated with widespread pain.[167,168] In this review, we highlight the role of glial cells and neuroinflammation in promoting central sensitization and widespread chronic pain. In 1983, Woolf[36] presented evidence for a central component of postinjury pain hypersensitivity. The International Association for the Study of Pain describes central sensitization as increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.[169] Central sensitization may also include conditions like increased central responsiveness due to dysfunction of endogenous pain control systems, regardless of whether there is functional change of peripheral neurons. In 2003, Ji et al.[6] defined central sensitization as the increased synaptic efficacy established in somatosensory neurons in the dorsal horn of the spinal cord after intense peripheral noxious stimuli, tissue injury, or nerve damage. This heightened synaptic transmission results in a reduction in pain threshold, an amplification of pain responses, and a spread of pain sensitivity to noninjured areas. In 2009, Latremoliere and Woolf[38] described central sensitization as an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy, as well as to reduced inhibition, and as a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. In this review, the authors highlighted disinhibition (reduced inhibition) and also emphasized that the net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification.

Mechanisms of Central Sensitization

As shown in figure 5, activation of NMDA receptors is an essential step in initiating and maintaining the central sensitization and pain hypersensitivity after tissue and nerve injury.[170,171] Glutamate is a primary excitatory neurotransmitter in the pain pathway. Under normal circumstances NMDA receptor channels are blocked by Mg2+ ions, but this blockade is removed by membrane depolarization after activation of nociceptive primary afferents. Activation of NMDA receptors boosts synaptic efficacy and causes Ca2+ influx, which can activate intracellular signaling pathways that initiate and maintain central sensitization.[6,38] In particular, tissue and nerve injury increases the expression of the NMDA receptor-NR2B (GluN2B) subunit, which regulates spinal synaptic plasticity in persistent pain conditions together with the NR1 subunit.[172] Interestingly, NR2B/GluN2B receptor activity and surface expression in spinal cord dorsal horn neurons is negatively regulated by β-arrestin 2,[173] a scaffold protein that was traditionally known as an inhibitor of G-protein–coupled receptors. Deficiency of β-arrestin 2 results in enhanced acute opioid analgesia, produced by morphine and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, a selective μ opioid receptor agonist.[173,174] Paradoxically, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin-induced hyperalgesia is also potentiated after β-arrestin 2 deficiency, as a result of enhanced surface and synapse expression of GluN2B that results in hyperactivity of the receptor. Loss of β-arrestin 2 also leads to a prolongation of inflammatory and neuropathic pain, because these pain conditions critically depend on GluN2B.[173] It appears that for the resolution of persistent pain, it is more important for β-arrestin 2 to regulate NMDA receptors via extracellular signal-regulated kinase signaling pathway (Figure 5). Furthermore, surface trafficking of AMPA receptors, especially calcium-permeable subunit (GluR1/GluR-A), plays a critical role in spinal cord synaptic plasticity and pain hypersensitivity after tissue injury.[175,176] The scaffold protein Homer1a operates in a negative feedback loop to regulate calcium signaling and the excitability of the spinal cord pain pathway in an activity-dependent manner.[177] Given a critical role of AMPA receptor in direct control of excitatory synaptic transmission in pain circuits, NMDA receptor–independent central sensitization may also exist.

Figure 5.

Molecular mechanisms of central sensitization in first-order excitatory synapses in the spinal cord dorsal horn pain circuit and induction of central sensitization by proinflammatory cytokines and chemokines (e.g., tumor necrosis factor [TNF], interleukin [IL]-1β, chemokine [CC motif] ligand 2 [CCL2], chemokine [CXC motif] ligand 1 [CXCL1]) that are produced by glial cells. At presynaptic sites (i.e., central terminals of nociceptive primary afferents), activation of receptors of cytokine and chemokine receptors results in phosphorylation and activation of extracellular signal-regulated kinase (P-ERK) and p38 (P-p38), leading to glutamate (Glu) release from synaptic vesicles via activation of ion channels transient receptor potential ion channel V1, voltage-gated sodium ion channel 1.7 (Nav1.7), and voltage-gated sodium channel subtype 1.8 (Nav1.8). At postsynaptic sites, increased release of neurotransmitters (e.g., glutamate) also induces phosphorylated extracellular signal-regulated kinase, which can induce central sensitization by positive modulation of N-methyl-D-aspartate receptor (NMDAR, step 1). Positive regulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR, step 2) and negative modulation of potassium channel subunit Kv4.2 (step 3) are also shown. Phosphorylated extracellular signal-regulated kinase also maintains central sensitization via inducing cAMP response element–binding protein phosphorylation (P-CREB, step 4). CREB is a critical transcription factor that controls the expression of pronociceptive genes. Opioids such as morphine inhibit neurotransmitter release via μ opioid receptors (MOR) and N-type calcium channels. The scaffold protein β-arrestin 2 (βarr2) inhibits μ opioid receptor signaling by desensitization and degradation of G-protein–coupled receptors, leading to enhanced acute opioid analgesia in β-arrestin 2 knockout mice. Paradoxically, β-arrestin 2 also inhibits N-methyl-D-aspartate receptor and extracellular signal-regulated kinase signaling, leading to a transition from acute pain to chronic pain.174 CXCR2 = CXC motif chemokine receptor 2; IL-1R = interleukin-1 receptor; TNFR = tumor necrosis factor receptor.

Activation of intracellular pathways by protein kinases, such as protein kinase A, protein kinase C, Ca2+/calmodulin-dependent kinase II, Src (a tyrosine kinase encoded by sarcoma oncogene), and extracellular signal-regulated kinases (including extracellular signal-regulated kinases 1 and 2), is important for the generation of central sensitization.[6,37,178] Notably, activation of extracellular signal-regulated kinase via phosphorylation of extracellular signal-regulated kinase in spinal cord dorsal horn neurons is nociceptive-specific and serves as a marker of central sensitization.[179–181] Phosphorylation of extracellular signal-regulated kinase is a common pathway after the activation of various ionotropic and metabotropic receptors and protein kinases (protein kinase A, protein kinase C, and Src) as well as a downstream event of Ca2+ signaling.[182–184] Phosphorylation of extracellular signal-regulated kinase induces central sensitization via rapid posttranslational regulation, such as suppression of potassium channel Kv4.2 activity, leading to hyperactivity of the spinal cord dorsal horn.[185,186] Phosphorylation of extracellular signal-regulated kinase also contributes to rapid upregulation of NMDA receptor (GluN2B) function in spinal cord dorsal horn neurons in response to inflammatory mediators.[150,187] Furthermore, translocation of phosphorylated extracellular signal-regulated kinase to the nuclei of spinal cord dorsal horn neurons activates the transcription factor cAMP response element–binding protein, leading to increased expression of pronociceptive genes encoding for c-Fos, NK-1, and prodynorphin.[182,188]

Does Central Sensitization Require Peripheral Input?

Historically, it has been believed that the central sensitization to noxious stimuli requires sustained, intense, and repeated applications of the stimulus. More recently, it has become apparent that persistent peripheral nociceptive input may not be required to elicit central sensitization, because central sensitization can result from changes in the properties of neurons in the central nervous system that appear to be independent of peripheral input.[38] Central sensitization produces pain hypersensitivity by changing the sensory responses elicited by normal inputs, including subthreshold innocuous tactile stimulation. For example, spinal cord disinhibition by intrathecal injection of γ-aminobutyric acid (GABA) and glycine receptor antagonists is sufficient to induce central sensitization and mechanical allodynia via disinhibition of inhibitory signaling and subsequent activation of excitatory signaling that is mediated by the NMDA receptor.[189] Disinhibition of γ-aminobutyric acid–mediated (GABAergic) and glycinergic synaptic transmission in the spinal cord pain circuitry is critical to the generation of chronic pain.[84–87] Gate control theory describes a tonic inhibition of the spinal cord pain circuit via inhibitory neurons.[190] A feed-forward spinal cord glycinergic neural circuit in the laminae II–III dorsal horn gates mechanical allodynia, and nerve injury impairs glycinergic synaptic transmission and opens the gate to elicit mechanical allodynia.[84]

It is noteworthy that some central etiologies/injuries such as spinal cord injury, traumatic brain injury, and multiple sclerosis may cause neuroinflammation, central sensitization, and chronic pain without a peripheral insult (Figure 2).[191] Therefore, it is important for future studies to examine neuroinflammation in the brain, including those regions that do not receive input from primary afferents. Spinal cord injury is sufficient to produce hyperexcitability in primary sensory neurons[192] via possible retrograde signaling from the dorsal root reflex. Neuroinflammation in the spinal cord may also regulate gene expression of primary sensory neurons via diffusible inflammatory mediators that can reach to dorsal root ganglia. Thus, there could be bidirectional interactions between peripheral sensitization and central sensitization. Central sensitization is not only secondary to peripheral sensitization but may, in turn, regulate peripheral sensitization (Figure 4).

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