Abstract

The current clinical management of neuropathic pain remains a real and big challenge to clinicians.

The last 3 decades have witnessed an explosion of research in the molecular neurobiology of pain. The traditional belief that pain modulation is solely based on peripheral and central pain pathways or based on peripheral pain modulators such as bradykinin, substance P and prostaglandin, is becoming secondary and redefined, albeit still valid. The novel look emphasizes on the role of glial cells (Mainly microglia and astrocytes) in the dorsal horn of the spinal cord, and their intricate communication with neurons. Similarly, the presumed passive physiologic role of glial cells being simply related to housekeeping like supporting, maintaining, repairing, nurturing, and protecting the neurons is becoming a mediocre definition. Glial cells, especially microglia, once activated, are found to orchestrate the initiation of pain processes, whereas astrocytes are responsible for pain maintenance. Once triggered, glial activation causes proliferation, morphological changes, and expression of receptors and markers (e.g. glial fibrillary acidic protein (GFAP)) that lead to the production inflammatory mediators (e.g. tumor necrosis factor-, interleukin-1, interleukin-6 (IL-6), nerve growth factor (NGF)), growth factors (brain-derived growth factor (BDNF) and basic fibroblast growth factor (bFGF)), cytokines and chemokines (e.g. MCP-1, CX3CL1, CCL2, CXCL13, CXCR5). This activation can have severe and deleterious effects on pain symptoms and trigger and maintain a serious pain syndrome. This ambivalent function of glial cell activation is the focus of our review manuscript. We feel it is important to understand these mechanisms as these may shed light on potential novel treatment options of neuroinflammation and neuropathic pain. It is important to understand that we have based our review on research on animals and the same may or may not apply for humans, and we have focused mainly on microglia and astrocytes.

Keywords: Glia; Microglia; Astrocytes; Neuropathic Pain; Pain; Neuroinflammation; Chemokines; Cytokines; Glial Activation

References

1. International Association for the Study of Pain. IASP Taxonomy. Pain terms. Neuropathic pain (2017). 
2. Galambos R. “A glia-neural theory of brain function”. Proceedings of the National Academy of Sciences of the United States of America 47.1 (1961): 129-136. 
3. Moalem G and Tracey DJ. “Immune and inflammatory mechanisms in neuropathic pain”. Brain Research Reviews 51 (2006): 240-264.
4. Latremoliere A and Woolf CJ. “Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity”. The Journal of Pain 10.9 (2009): 895-926. 
5. Ikeda H., et al. “Synaptic Plasticity in the Spinal Dorsal Horn”. Journal of Neuroscience Research 64.2 (2009): 133-136.
6. Yaksh TL. “Central pharmacology of nociceptive transmission”. Elsevier, Churchill Livingtone (2006). 
7. Ren K and Dubner R. “Pain Facilitation and Activity-Dependent Plasticity in Pain Modulatory Circuitry: Role of BDNF-TrkB Signaling and NMDA Receptors”. Molecular Neurobiology 35 (2007): 224-235 (2007). 
8. Coull, J., et al. “BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain”. Nature 438 (2005): 1017-1021. 
9. Garrison CJ., et al. “Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury”. Brain Research 565.1 (1991): 1-7. 
10. Baptista MJ., et al. “Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease”. Neuroscientist 10.1 (2004): 63-72.
11. Hansson E. “Long-term pain, neuroinflammation and glial activation”. Scandinavian Journal of Pain1.2 (2010). 
12. Carson MJ., et al. “The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival”. Clinical Neuroscience Research 6.5 (2006): 237-245. 
13. Moalem G and Tracey DJ. “Immune and inflammatory mechanisms in neuropathic pain”. Brain Research Reviews 51.2 (2006): 240-264.
14. Kriegstein A and Alvarez-Buylla A. “The glial nature of embryonic and adult neural stem cells”. The Annual Review of Neuroscience 32 (2009): 149-184.
15. Jha MK., et al. “Glia as a Link between Neuroinflammation and Neuropathic Pain”. Immune Network 12.2 (2012): 41-47. 
16. Ji RR., et al. “Glia and pain; is chronic pain a gliopathy?” The Journal of Pain 154.1 (2013): S10-S28. 
17. DeLeo JA., et al. “Immune and glial regulation of pain”. Seattle: IASP Press (2007). 
18. Ren K and Dubner R. “Neuron-glia crosstalk gets serious: Role in pain hypersensitivity”. Current Opinion in Anesthesiology 21.5 (2008): 570-579. 
19. Wen YR., et al. “Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model”. Anesthesiology 107 (2007): 312-321.
20. Zhuang ZY., et al. “ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model”. Pain 114.1-2 (2005): 149-159.
21. Sung B., et al. “Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats”. The Journal of Neuroscience 23.7 (2003): 2899-2910.
22. Spataro LE., et al. “Spinal gap junctions: potential involvement in pain facilitation”. The Journal of Pain 5.7 (2004): 392-405.
23. Tanga FY., et al. “The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy”. Proceedings of the National Academy of Sciences of the United States of America 102.16 (2005): 5856-5861.
24. Griffin RS., et al. “Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity”. The Journal of Neuroscience 27 (2007): 8699-8708.
25. Tanga FY., et al. “Role of astrocytic S100beta in behavioral hypersensitivity in rodent models of neuropathic pain”. Neuroscience 140.3 (2006): 1003-1010.
26. Nakajima K and Kohsaka S. “Microglia: activation and their significance in the central nervous system”. Journal of Biochemistry 130.2 (2001): 169-175.
27. Graeber MB., et al. “Microglial cells but not astrocytes undergo mitosis following rat facial nerve axotomy”. Neuroscience Letters 85.3 (1988): 317-321.
28. Watkins LR., et al. “Chapter 22 Contribution of glia to pain processing in health and disease”. Handbook of Clinical Neurology 81 (2006): 309-323.
29. Li T., et al. “An update on reactive astrocyte in chronic pain”. Journal of Neuroinflammation 16 (2019): 140. 
30. Liddelow SA., et al. “Neurotoxic reactive astrocytes are induced by activated microglia”. Nature 541.7638 (2017): 481-487.
31. Fujita A., et al. “Connexin 30 deficiency attenuates A2 astrocyte responses and induces severe neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride Parkinson's disease animal model”. Journal of Neuroinflammation 15.1 (2018): 227.
32.  Pekny M., et al. “Astrocytes: a central element in neurological diseases”. Acta Neuropathologica 131.3 (2016): 323-345. 
33. Ji RR., et al. “MAP kinase and pain”. Brain Research Reviews 60.1 (2009): 135-148. 
34. Kumar S., et al. “p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases”. Nature Reviews Drug Discovery 2 (2003): 717-726.
35. Ji RR., et al. “p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia”. Neuron 36 (2002): 57-68. 
36. Cui Y., et al. “Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance”. Brain Research 1069 (2006): 235-243. 
37. Raghavendra V., et al. “Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS”. European Journal of Neuroscience 20.2 (2004): 467-473.
38. DeLeo JA and Winkelstein BA. “Physiology of chronic spinal pain syndromes: from animal models to biomechanics”. Spine 27.22 (2002): 2526-2537.
39. White FA., et al. “Chemokines and the pathophysiology of neuropathic pain”. Proceedings of the National Academy of Sciences of the United States of America 104.51 (2007): 20151-20158.
40. Verge GM., et al. “Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions”. European Journal of Neuroscience 20.5 (2004): 1150-1160.
41. Zhuang ZY., et al. “Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine”. Brain, Behavior, and Immunity 21.5 (2007): 642-651.
42. Sun S., et al. “New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis”. Pain 129.1-2 (2007): 64-75.
43. Zhang ZJ., et al. “Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain”. Cellular and Molecular Life Sciences 74.18 (2017): 3275-3291. 
44. Gosselin RD., et al. “Glial cells and chronic pain”. Neuroscientist 16.5 (2010): 519-531. 
45. Scholz J and Woolf CJ. “The neuropathic pain triad: neurons, immune cells and glia”. Nature Neuroscience 10.11 (2007): 1361-1368.
46. Hanani M. “Satellite glial cells in sensory ganglia: from form to function”. Brain Research Reviews 48.3 (2005): 457-476.
47. Pertin M., et al. “Delayed sympathetic dependence in the spared nerve injury (SNI) model of neuropathic pain”. Molecular Pain 3 (2007): 21.
48. Zhou XF., et al. “Satellite-cell-derived nerve growth factor and neurotrophin-3 are involved in noradrenergic sprouting in the dorsal root ganglia following peripheral nerve injury in the rat”. European Journal of Neuroscience 11.5 (1999): 1711-1722.
49. Liu FY., et al. “Activation of satellite glial cells in lumbar dorsal root ganglia contributes to neuropathic pain after spinal nerve ligation”. Brain Research 1427 (2012): 65-77. 
50. Del Valle L., et al. “Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome”. Brain, Behavior, and Immunity 23.1 (2009): 85-91. 
51. Brisby H., et al. “Markers of nerve tissue injury in the cerebrospinal fluid in patients with lumbar disc herniation and sciatica”. Spine 24.8 (1999): 742-746.
52. Papandreou O., et al. “Serum S100beta protein in children with acute recurrent headache: a potentially useful marker for migraine”. Headache 45.10 (2005): 1313-1316.

Citation

Citation: Bilal F Shanti., et al. “The Ambivalent Role of Glial Cells in Neuroinflammation and Neuropathic Pain”. Acta Scientific Neurology 3.6 (2020): 51-58.

Copyright

Copyright: © 2020 Bilal F Shanti., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.