Glial cells and chronic pain

Abstract

Over the past few years, the control of pain exerted by glial cells has emerged as a promising target against pathological pain. Indeed, changes in glial phenotypes have been reported throughout the entire nociceptive pathway, from peripheral nerves to higher integrative brain regions, and pharmacological inhibition of such glial reactions reduces the manifestation of pain in animal models. This complex interplay between glia and neurons relies on various mechanisms depending both on glial cell types considered (astrocytes, microglia, satellite cells, or Schwann cells), the anatomical location of the regulatory process (peripheral nerve, spinal cord, or brain), and the nature of the chronic pain paradigm. Intracellularly, recent advances have pointed to the activation of specific cascades, such as mitogen-associated protein kinases (MAPKs) in the underlying processes behind glial activation. In addition, given the large number of functions accomplished by glial cells, various mechanisms might sensitize nociceptive neurons including a release of pronociceptive cytokines and neurotrophins or changes in neurotransmitter-scavenging capacity. The authors review the conceptual advances made in the recent years about the implication of central and peripheral glia in animal models of chronic pain and discuss the possibility to translate it into human therapies in the future.

Figure 1

Schematic representation of glial events occurring in normal nociceptive state: under basal condition, acute pain signaling is likely not influenced by microglial cells in a resting stage. Conversely, astrocytes are actively involved in neuronal physiology, particularly the reuptake of glutamate and GABA. This continuous glutamate and GABA reuptake by astrocytic processes around synapses between sensory afferents and inhibitory interneurons respectively allows a fast and regulated nociceptive neurotransmission toward upper brain regions.

Figure 2

Photomicrographs illustrating the glial reaction in the ipsilateral rat spinal cord and its various aspects 7 days after peripheral nerve injury (spared nerve injury model, SNI). A-B, double immunofluorescence labeling showing that both astrocytic marker GFAP (red) and microglial protein Iba-1 (green) are upregulated in the ipsilateral dorsal horn (A) in comparison to the contralateral side (B). Microglial reaction may also be visualized by labeling the integrin CD11-b (C-F). In neuropathic animals (E-F), an increase in CD11b immunoreacivity is observed ipsilaterally to the lesion site (E) in comparison to contralateral side (F) and spinal cord from sham-operated animals (C-D). Inserts in C and E show high magnification images of CD11-b labeled microglia from sham or neuropathic rats respectively. Note the change in cell shape in neuropathic animals, from ramified to activated form. Images are from personal unpublished data library.

Figure 3

Activation of p38 MAPK in the spinal cord subsequently to nerve injury in the Spinal Nerve Ligation (SNL) model of neuropathic pain. A, immunofluorescence labeling showing an increase level of phosphorylated p38 in the spinal cord ipsilaterally to the lesion site, 3 days post-surgery. B, kinase assay showing a fostered activity of p38-MAPK in neuropathy. An elevated capacity of p38 SNL spinal extracts to phosphorylate its substrate ATF-2 in comparison to naive extracts is obvious one day and 3 days post surgery. C-E, dual immunofluorescence showing that phosphorylated p38-MAPK does not colocalize with neuronal marker NeuN (C), astrocytic protein GFAP (D) but instead is present in microglia as assessed by the overlapping signal using the OX-42 antibody, detecting microglial CD11-b (E). Adapted from (Ji and others 2007).

Figure 4

Schematic illustartion of microglial (A) and astrocytic (B) events taking place in the spinal cord in neuropathic pain. A: In chronic neuropathic pain, under the influence of neuronal factors (such as CX3CL1, ATP or neuromediators), microglia undergoes changes in phenotype including an activation of p38 MAPK pathway. So-called activated microglia releases factors (such as cytokines) that in turn reinforce nociception by reducing the potency of GABAergic inhibition, sensitizing spinal neurons and activating astrocytes. B: An astrocytic activation also occurs (characterized by an activation of the intracellular JNK pathway) consequently to both neuronal releases of high amounts of neuromediators and microglial production of cytokines such as TNF-α. As a result of astrocyte reaction, a reduction of glutamate scavenging capacity together with an increase in GABA uptake reinforces pain signaling as well. Furthermore, reactive astrocyte release cytokines such as CCL2, participating in the loss of the GABAergic inhibition.

Figure 5

Nerve block inhibiting the activity of large Aβ fibers reduces the activation of p38 MAPK in spinal microglia in the rat spared nerve injury (SNI) model of neuropatic pain. A-D, immunofluorescence micrographs depicting the effects of nerve blocks on spinal p38 phosphorylation following surgery. An increase in p38 phosphorylation is obvious following SNI (B) in comparison to control spinal cord (A). Blocking nociceptive C and Aδ fibers conduction using pre-surgical Resiniferatoxin (RTX) is ineffective in reducing microglial p38 phosphorylation (C) whereas non-nociceptive (Aβ fibers) nerve block with Bupivacain (Bup) results in a striking inhibition of p38 activation (D). The bar histogram shown in E shows the corresponding cell count quantifications. Complementary methodological informations and discussion details may be found in the related article (Suter and others 2009).