Central sensitization: a generator of pain hypersensitivity by central neural plasticity

Abstract

Central sensitization represents 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 is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. 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. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations.

Perspective: In this article, we review the major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.

Figures

Figure 1

Subthreshold synaptic inputs. The substrate for receptive field plasticity. Intracellular in vivo recordings from a nociceptive-specific rat dorsal horn neuron revealing subthreshold synaptic inputs. The output of somatosensory neurons is determined by those peripheral sensory inputs that produce sufficiently large-amplitude monosynaptic and polysynaptic potentials to evoke an action potential discharge (A and B). This constitutes the receptive field or firing zone of the neuron. However, stimuli outside the receptive field can evoke synaptic inputs that are too small normally to produce action potential outputs (C), and this constitutes a subliminal fringe or low-probability firing fringe, which can be recruited if synaptic efficacy is increased, to expand and change the receptive field. In this particular neuron, a standard pinch stimulus applied to points A, B, and C evoked only action potentials at points A and B but clear subthreshold synaptic inputs at C. Modified from Reference 365.

Figure 2

Expansion of receptor fields during central sensitization. Recruiting subthreshold synaptic inputs to the output of a nociceptive-specific neuron can markedly alter its receptive field properties, producing changes in receptive field threshold and spatial extent. When neurons in the dorsal horn spinal cord are subject to activity-dependent central sensitization, they exhibit some or all the following: development of or increases in spontaneous activity, a reduction in threshold for activation by peripheral stimuli, increased responses to suprathreshold stimulation, and enlargement of their receptive fields. The examples in this figure of intracellular recordings of rat dorsal horn neurons show the cutaneous receptive fields before central sensitization (pre mustard oil) and after the induction of central sensitization (post mustard oil) and indicate how subthreshold nociceptive (pinch, top) and low-threshold (brush, bottom) inputs in the low-probability firing fringe (LPFF) are recruited by central sensitization. Central sensitization was produced by topical application of mustard oil, which generates a brief burst of activity in TRPA1-expressing nociceptors and resulted in the neural equivalent of secondary hyperalgesia (top) and tactile allodynia (bottom). Note that the mustard oil (conditioning input) was applied to a different area (in red) from the test pinch or brush inputs (in blue), so that the changes observed are due to hetero-synaptic facilitation. Modified from Reference 364.

Figure 3

Schematic representation of the structures exhibiting central sensitization. The first evidence for central sensitization was generated in 1983 by revealing injury-induced changes in the cutaneous receptive field properties of flexor motor neurons as an integrated measure of the functional plasticity in the spinal cord. A conditioning noxious stimulus resulted in long-lasting reductions in the threshold and an expansion of the receptive field of the motor neurons that was shown to be centrally generated. Essentially identical changes were then described in lamina I and V neurons in the dorsal horn of the spinal cord (b) as well as in spinal nucleus pars caudalis (Sp5c), thalamus (c), amygdala, and anterior cingulate cortex. Imaging techniques have revealed several brain structures in human subjects that exhibit changes compatible with central sensitization (blue dots).

Figure 4

Central sensitization triggers: Schematic representation of key synaptic triggers of central sensitization. (A), Model of the synapse between the central terminal of a nociceptor and a lamina I neuron under control, basal conditions. mGluR receptors sit at the extremities of the synapse and are linked to the endoplasmic reticulum (ER). Note that NMDAR channels are blocked by Mg2+ in the pore (black dot). After a barrage of activity in the nociceptor (B), the primary afferent presynaptic terminal releases glutamate that binds to AMPAR, NMDAR (now without Mg2+), and mGluR, as well as substance P, CGRP, and BDNF, which bind to NK1, CGRP1, and TrkB receptors, respectively. B2 receptors are also activated by spinally produced bradykinin. NO is produced by several cell types in the spinal cord and can act presynaptically and postsynaptically.

Figure 5

Sources of Ca2+ in the synapse of nociceptive neurons for inducing central sensitization. (A), Model of a nociceptor–dorsal horn neuron synapse under control, nonactivated conditions. After nociceptor input (B), activation of NMDAR and mGluR result in a rapid increase of [Ca2+]i that activates PKC and CaMKII, 2 major effectors of central sensitization. (C), Representation of a synapse during peripheral inflammation-induced central sensitization, where there is a shift from GluR2/3 to GluR1-containing AMPARs that enables, along with voltage-dependent calcium channels and NMDAR, entry of Ca2+ and which, together with activation of the G-coupled MGluR, NK1, B2, and CGRP1 receptors, which release intracellular Ca2+ stores, recruits PKC and CaMKII, strengthening the excitatory synapse.

Figure 6

Contribution of PKC, CaMKII, PKA, and ERK activation to central sensitization. (A), Phosphorylation by PKC, CaM-KII, PKA, and ERK cause changes in the threshold and activation kinetics of NMDA and AMPA receptors, boosting synaptic efficacy. ERK also produces a decrease in K+ currents through phosphorylation of Kv4.2 channels, increasing membrane excitability. (B), PKA, CaMKII, and ERK promote recruitment of GluR1-containing AMPAR to the membrane from vesicles stored under the synapse. (C), Transcriptional changes mediated by activation of CREB and other transcription factors driving expression of genes including c-Fos, NK1, TrkB, and Cox-2, to produce a long-lasting strengthening of the synapse.

Figure 7

Key effectors of central sensitization in the dorsal horn. Subcutaneous injection of capsaicin, a potent inducer of central sensitization, causes rapid activation of ERK and CREB (upper panels) as well as a PKC-induced phosphorylation of the NR1 subunit of NMDAR in c-Fos–positive neurons of the superficial laminas of the spinal cord (middle panels). ERK activation participates in transcriptional and post-translational changes, CREB activation promotes transcription of several genes involved in central sensitization. NR1 phosphorylation by PKC increases NMDAR activity. ERK and PKC are activated through the increase of intracellular calcium that occurs during stimulation of nociceptive fibers (lower panels). Signals are shown in pseudocolor from blue (weak intensity) to red (strong intensity). ERK and CREB staining are from Reference 141; NR1 phosphorylation staining from Reference 32, and calcium imaging from Reference 179.

Figure 8

Key intracellular pathways contributing to the generation of central sensitization. NMDAR activation causes activation of PKC, CaMKII, and ERK (black arrows); GluR1-containing AMPAR activate PKC (red arrow); NK1 and CGRP1 receptors activate PKC, PKA, and ERK (orange and brown arrows, respectively); TrkB s activates of PKC and ERK (purple arrows); and mGluR, via release of Ca2+ from microsomal stores, activates PKC and ERK (gray arrows). Note that most of the triggers of central sensitization: Activation of NMDAR, mGluR, TrkB, NK1, CGRP1, or B2 converge to activate ERK.

Figure 9

Multiple cellular processes lead to central sensitization. Central sensitization is not defined by activation of a single molecular pathway but rather represents the altered functional status of nociceptive neurons. During central sensitization, these neurons display 1 or all of the following: i, development of or an increase in spontaneous activity; ii, reduction in threshold for activation; and iii, enlargement of nociceptive neuron receptive fields. These characteristics can be produced by several different cellular processes including increases in membrane excitability, a facilitation of synaptic strength, and decreases in inhibitory transmission (disinhibition). Similarly, these mechanisms can be driven by different molecular effectors including PKA, PKC, CaMKII, and ERK1/2. These kinases participate in changes in the threshold and activation kinetics of NMDA and AMPA receptors and in their trafficking to the membrane, cause alterations in ion channels that increase inward currents and reduce outward currents, and reduce the release or activity of GABA and glycine.

Figure 10

Homo synaptic and heterosynaptic facilitation. (A), Homosynaptic potentiation is a form of use-dependent facilitation of a synapse evoked by activation of that same synapse (in red). A nonconditioned synapse (green) is not potentiated. This type of potentiation is commonly called long-term potentiation (LTP). LTP-like homosynaptic potentiation can contribute to primary hyperalgesia. (B), Heterosynaptic facilitation represents a form of activity-dependent facilitation in which activity in 1 set of synapses (conditioning input, red) augments subsequent activity in other, nonactivated groups of synapses (test input, green). Heterosynaptic potentiation is responsible for the major sensory manifestations of use-dependent central sensitization: pain in response to low-threshold afferents (allodynia) and spread of pain sensitivity to noninjured areas (secondary hyperalgesia).

Figure 11

Action potential windup. Windup is the consequence of a cumulative membrane depolarization resulting from the temporal summation of slow synaptic potentials. Under normal conditions, low-frequency stimulations of C-fibers (0.2 Hz) cause steady neuronal discharges (A) as the membrane potential has sufficient time to return to resting potential between stimuli. At a frequency of 0.5 Hz or higher, activation of NK1 and CGRP1 receptors by release of substance P and CGRP from peptidergic nociceptors produces a cumulative increase in membrane depolarization. This then enables activation of NMDAR by removal of the voltage-dependent Mg2+ block, further boosting the responses in a non-linear fashion (B). Windup disappears within tens of seconds of the end of the stimulus train as the membrane potential returns to its normal resting level (B). Modified from Reference 323.

Figure 12

Central sensitization in pathological settings. A, Representation of the superficial lamina of the dorsal horn of the spinal cord. Nociceptive peptidergic fibers contact lamina I and II outer (I and IIo) neurons that express GluR2-containing AMPAR (in blue). Some of these neurons project to the thalamus, parabrachial nucleus, and PAG. Nociceptive nonpeptidergic fibers contact neurons in dorsal lamina II inner (IIid), which also express GluR2-containing AMPAR. Non-nociceptive large fibers contact deeper laminae but also send collaterals to inhibitory interneurons in the ventral part of lamina II (IIiv). B, Alterations in the superficial lamina in inflammatory pain. Because large DRG neurons begin to express SP and BDNF, stimulation of these afferents acquires the capacity to generate central sensitization. Neurons now express GluR1-containing AMPAR at their synapse (in red), resulting in an increase of Ca2+ influx on their activation. Some spinal cord microglial cells are activated and release factors that contribute to the development of central sensitization by enhancing excitatory and reducing inhibitory currents. C, Representation of superficial lamina in neuropathic pain states. After peripheral nerve injury, there is a loss of C-fiber central terminals and the sprouting of myelinated A-β fibers from deep to superficial lamina. Injured sensory neurons in the dorsal root ganglion exhibit a change in transcription that alters their membrane properties, growth, and transmission. Large fibers begin to express substance P, BDNF, and the synthetic enzymes for tetrahydrobiopterin, an essential cofactor for NOS and can drive central sensitization. Recruitment and activation of microglial cells is an essential step in the development of pain after nerve injury and to trigger central sensitization by releasing proinflammatory cytokines that increase neuronal excitability and BDNF that induces a switch in Cl- gradients, resulting in a loss of inhibition. Loss of inhibition is also caused by excitotoxic apoptosis of inhibitory interneurons.

Figure 13

Role of scaffolding proteins in central sensitization. Representation of the post synaptic density (PSD) region of a synapse of a nociceptive neuron in the superficial lamina of the spinal cord under basal conditions (A) and during inflammatory pain (B). The proteins that make up the PSD can drive a major functional reorganization of synapses, modifying postsynaptic efficacy by altering receptor density at the membrane and producing switches from Ca2+-impermeable to Ca2+-permeable AMPARs. In addition, scaffolding proteins mediate the “addressing” of kinases to the receptors, thereby increasing their activity. Under normal conditions (A), neurons mostly express GluR2-containing AMPAR that are anchored to the PSD via GRIP-1. NMDAR are recycled in an activity-dependent manner via PICK-1 and NSF. During inflammation (B), there is an endocytosis of GluR2-containing AMPAR (initiated by PKC phosphorylation of GluR2) along with a loss of NSF that prevents their reinsertion into the synapse. GluR1-containing AMPAR are expressed at the membrane, where their activity is increased by phosphorylation with PKA as well as by the ectodomain of stargazin, whose C-terminus segment is phosphorylated by PKC and CaMKII. MAGUK can participate to increase glutamate receptors density at the synapse, and phosphorylated stargazin promotes AMPAR and NMDAR clustering. Scaffolding proteins such as AKAP79/150 and the MAGUKs also “address” kinases to specific synaptic position at the right time to phosphorylate AMPAR and NMDAR subunits, thereby increasing their activity. The Homer-Shank1-GKAP-MAGUK complex couples mGluR and NMDAR to intrasomal Ca2+ stores, so that activation of glutamate receptors leads to high levels of Ca2+ in the PSD that activate PKC and CaMKII, also recruited to the PSD by scaffolding proteins. PKC, CaMKII, and other kinases converge to activate ERK, which reduce K+ channels activity and promote transcriptional activity.

Figure 14

Synaptic scaffolding proteins and the switch to GluR1-containing AMPAR after peripheral inflammation. Under basal conditions, GluR2-containing AMPARs are associated in the synapse with stargazin and GRIP-1. The C-terminus of stargazin binds to PSD-95 (1). Peripheral inflammation leads to glutamate release from nociceptors and AMPA and NMDA receptor activation. NMDAR activation leads to a Ca2+ influx that activates PKC (2). Activated PKC phosphorylates GluR2-containing AMPARs at ser880, which leads to a loss of affinity for stargazin and GRIP-1, allowing PICK-1 to bind to the receptor (3). The GluR2-containing AMPAR and PICK-1 complex undergo endocytosis, whereas NSF is downregulated, preventing reinsertion of GluR2-containing AMPAR into the synapse. Meanwhile, peripheral inflammation also leads to activation of PKA that promotes GluR1-containing AMPAR to be inserted into the membrane (4). Because GluR2-containing AMPARs are internalized and the Ca2+-permeable GluR1-containing AMPAR are inserted into the membrane, there is a switch from GluR2- to GluR1-containing AMPAR (5 and 6). Increased [Ca2+]i causes an activation of PKC and CaMKII, which phosphorylate the C-terminus of stargazin, increasing its affinity for PSD-95 (CaMKII) and modifying its ectodomain (PKC), which causes increased GluR1 affinity for glutamate and single-channel conductance and a higher channel opening probability, further increasing Ca2+ influx (7).