Glia and pain: is chronic pain a gliopathy?

Abstract

Activation of glial cells and neuro-glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. Although widely detected in chronic pain resulting from nerve trauma, inflammation, cancer, and chemotherapy in rodents, and more recently, human immunodeficiency virus-associated neuropathy in human beings, glial reaction (activation state 1) is not thought to mediate pain sensitivity directly. Instead, activation states 2 to 4 have been demonstrated to enhance pain sensitivity via a number of synergistic neuro-glial interactions. Glial mediators have been shown to powerfully modulate excitatory and inhibitory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites. Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of "gliopathy," that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions.

Keywords: ATP receptors; Astrocytes; Chemokines; Cytokines; Human; Microglia; Rodents; Satellite glial cells; Spinal cord.

Fig. 1

Different activation states of glia. Glia exhibit different activation states after painful injuries. (1) Glial reaction refers to upregulation of glial markers and morphological changes of glia (gliosis); (2) upregulation of glial receptors such as adenosine triphosphate (ATP) receptors, chemokine receptors, and Toll-like receptors, which will lead to the third activation state: (3) activation of intracellular signaling pathways, such as mitogen-activated protein kinase (MAPK) pathways. Phosphorylation of MAPKs will lead to the next activation state: (4) upregulation of glial mediators, such as cytokines, chemokines, and growth factors. Upon release, these glial mediators can interact with neurons to elicit pain via central and peripheral sensitization. Unlike glial reaction (state 1), the other activation states (states 2-4) have been shown to induce pain.

Fig. 2

Activation of microglia in the spinal cord dorsal horn 3 days after spared nerve injury (SNI) in rats. (A) IB4 staining in the spinal cord dorsal horn ipsilateral and contralateral to the injury side. Note a loss of IB4 staining in the dorsal horn region innervated by the injured nerve branches. (B and C) CD11b (OX-42) and phosphorylated p38 (p-p38) immunostaining in the dorsal horn ipsilateral and contralateral to the injury side. Note overlapping expression patterns of OX-42 and p-p38 in the injury side. (D) Double staining of p-p38 (red) and OX-42 (green) in the ipsilateral dorsal horn. Lower panel presents high-magnification images of 2 microglial cells (indicated by arrow and arrowhead) from the upper panel. Note that p-p38 is completely co-localized with OX-42. Scale, 100 lm. Images are modified from Wen et al. [276], with permission.

Fig. 3

Schematic of neuronal–glial and glial–glial interactions in the spinal cord in persistent pain. Spontaneous discharge after a painful injury (eg, nerve injury) results in the release of ATP, chemokines (CCL2, CCL21, CX3CL1), MMP-9, NRG1, and CRGP from primary afferent central terminals, leading to activation of microglia in the dorsal horn. Spinal microglia express the receptors for ATP (P2X4, P2X7, P2Y6, P2Y12), and chemokines (CX3CR1, CCR2), and NRG1 (ErB2). Activation of these receptors induces phosphorylation of p38 and ERK (early phase) in microglia, leading to the production and release of the proinflammatory cytokines (TNF-α, IL-1β, IL-18) and the growth factor BDNF, and the consequent sensitization of dorsal horn neurons. Astrocytes can be activated by microglial mediators (TNF-α and IL-18), as well as astrocytic mediators (matrix metalloprotein-2 (MMP-2) and bFGF). Subsequent phosphorylation of JNK and P-ERK in astrocytes results in the production and release of chemokines (eg, CCL2) and cytokines (eg, interleukin-1β [IL-1β]). Astrocytes also produce adenosine triphosphate (ATP) and glutamate after the activation of the hemichannels (Cx43 and PNX1). After nerve injury, downregulation of astrocytic GLT1 results in decrease in astrocytic uptake of glutamate. Release of astrocytic mediators (CCL2, interleukin-1β [IL-1β], glutamate) can elicit NMDAR-mediated central sensitization. Release of adenosine triphosphate (ATP) and CCL2 from astrocytes can further maintain microglial activation.

Fig. 4

Glial mediators modulate excitatory and inhibitory synaptic transmission in the spinal cord. (A) Modulation of excitatory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites by glial mediators. Presynaptically, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), CCL2, interferon-γ (IFN-γ), and TSP4 increase glutamate release to enhance EPSC frequency. Postsynaptically, IL-1β TNF-α, and CCL2 increase AMPAR activity. Extrasynaptically, TNF-α, IL-1β, CCL2, and D-serine increase NMDAR-NR2B activity and enhance NMDA-induced currents. Astrocyte-released glutamate can further induce NR2B-mediated inward currents in surrounding neurons. (B) Modulation of inhibitory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites. Presynaptically, IL-1β and IL-6 decrease GABA and glycine release to decrease IPSC frequency. Postsynaptically, IL-1β decreases GABA/GlyR activity and IPSC amplitude. Prostaglandin E₂(PGE₂) inhibits evoked glycine current. Extrasynaptically, IL-1β, CCL2, and IFN-γ suppress GABA-and/or glycine-induced currents. TNF-α inhibits action potentials in inhibitory neurons. In lamina I neurons, BDNF produces disinhibition by altering chloride reverse potential.

Fig. 5

Schematic representation of neuronal-glial interactions in dorsal root and trigeminal ganglia of the peripheral nervous system (PNS). Spontaneous neuronal discharge after painful injury results in adenosine triphosphate (ATP) release in neuronal somata, leading to the activation of P2X7 and subsequent release of tumor necrosis factor-α (TNF-α) in satellite glial cells (SGCs). Persistent nociceptive activity or activation of opioid receptors by morphine also results in matrix metalloproteinase-9 (MMP-9) release from primary sensory neurons, causing the cleavage (activation) and release of interleukin-1β (IL-1β) in SGCs. TNF-α and IL-1β bind respective TNFR and IL-1R on sensory neurons to elicit hyperexcitability. SGCs can also release ATP via hemichannels (Cx43 and PNX1) or gap junction communication to activate P2X3 in neurons for triggering peripheral sensitization. In addition, SGCs express Kir 4.1 to maintain homeostasis of extracellular K⁺levels of sensory neurons, and injury-induced downregulation of Kir4.1 in SGCs will disrupt this K⁺homeostasis and generate neuronal hyperexcitability.

Fig. 6

Glial fibrillary acidic protein (GFAP) immunostaining of mouse, rhesus monkey, and human astrocytes in cortex. Note striking differences in the sizes of mouse, monkey, and human astrocytes. Also note differences in the number and lengths of branches of astrocytes from mouse, monkey, and human being. Sizes of astrocytes increase with increasing complexity of brain function. Scale, 50 μm. Images are reproduced from Kimelberg and Nedergaard [133], with permission.