http://dx.doi.org/10.4110/in.2012.12.2.41 REVIEW ARTICLE pISSN 1598-2629 eISSN 2092-6685 Glia as a Link between Neuroinflammation and Neuropathic Pain Mithilesh Kumar Jha, Sangmin Jeon and Kyoungho Suk* Department of Pharmacology, Brain Science & Engineering Institute, Kyungpook National University School of Medicine, Daegu 700-422, Korea Contemporary studies illustrate that peripheral injuries acti- clude astrocytes and oligodendrocytes (2). Glial cells that vate glial components of the peripheral and central cellular were, up to several years ago, considered the ٘forgotten brain circuitry. The subsequent release of glial stressors or activat- cells,ٙ or neglected stepchildren of neuroscience, now act as ing signals contributes to neuropathic pain and neuroinflam- orchestrators in the tetrapartite synapse, and control of their mation. Recent studies document the importance of glia in activation state is crucial to the integrity of CNS function. the development and persistence of neuropathic pain and Recent technical advances and increased interest in elucidat- neuroinflammation as a connecting link, thereby focusing at- ing the role of non-neuronal cells of the CNS in both the tention on the glial pathology as the general underlying fac- physiological and pathophysiologial processes have cata- tor in essentially all age-related neurodegenerative diseases. There is wide agreement that excessive glial activation is a pulted these cells into the forefront of neuroscience research. key process in nervous system disorders involving the re- Glial cells do not conduct nerve impulses, and they provide lease of strong pro-inflammatory cytokines, which can trig- structural support for the brain, assisting in nervous system ger worsening of multiple disease states. This review will development, repair and maintenance, supplying nutrients briefly discuss the recent findings that have shed light on the and biosynthetic products to neurons, imparting metabolic molecular and cellular mechanisms of glia as a connecting functions to neurons, destroying and removing injured and link between neuropathic pain and neuroinflammation. dead neurons and, finally, regulating the neuronal micro- -Immune Network 2012;12(2):41-47] environment. The well known quote ٖthe neuron is the struc] tural and functional unit of the brainٗ has been challenged by a wealth of findings which have, to the contrary, in- INTRODUCTION troduced the ٖneuronal-glial complexٗ as the structural and functional unit of the brain. Glia regulate brain vasculature Glia and the blood-brain barrier, modulating ischemia and -Gliaٙ refers to a diverse set of specialized cell types that are migraines. Moreover, they are important in the repair of neu٘ found both in the peripheral nervous system (Schwann cells, rons after injury and also contribute to neuropathology in satellite glia, perineural glia) and in the central nervous sys- neurodegenerative diseases. Microglia can either protect or tem (CNS) (astrocytes, oligodendrocytes, microglia, and peri- damage neurons depending on where and how they are vascular glia) (1). Glial cells constitute 70% of the total cell activated. Microglia are chronically engaged in repairing mi- population in the brain and spinal cord. Glial cells can be nor insults and that clinical diseases are observed only when subdivided into two primary categories: microglia, comprising these repair efforts fail. Fully activated microglia are detri- 5% to 10% of the glial population, and macroglia, which in- mental to neurons, but other stages in the sequence of re- Received on February 2, 2012. Revised on February 15, 2012. Accepted on February 17, 2012. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribu- tion, and reproduction in any medium, provided the original work is properly cited. *Corresponding Author. Tel: 82-53-420-4835; Fax: 82-53-256-1566; E-mail: [email protected] Keywords: Neuroinflammation, Astrocyte, Microglia, Glial activation, Pain IMMUNE NETWORK http://www.ksimm.or.kr Volume 12 Number 2 April 2012 41 Glia in Neuropathic Pain and Inflammation Mithilesh Kumar Jha, et al. active states may improve neuronal survival by releasing neu- cord), having occurred following viral infection, trauma, cer- rotrophic factors or by removing excess glutamate from the tain medications, or metabolic insults, and many diseases extracellular space (3). Glial cells, which include oligoden- such as MS and stroke, is especially problematic because of drocytes, astrocytes, and microglia, have been found to play its severity, chronicity, and resistance to simple analgesics key roles in neuroinflammation and neuropathic pain. Given (24). The possible mechanisms of neuropathic pain could be that less is known about the involvement of oligodendrocytes, classified as: a) chemical excitation of non-nociceptors, b) re- this paper will focus primarily on the role of astrocytes and cruitment of nerves outside the site of injury, c) excitotoxicity, microglial cells in neuroinflammation and neuropathic pain. d) excess sodium channels, e) ectopic discharge, f) central In view of the neuroinflammation and neuropathic pain proc- sensitization maintained by peripheral input, and g) sym- esses, activation of glial cells in the spinal dorsal horn, espe- pathetic involvement. cially microglia and astroglia, plays a predominant role. Furthermore, astrocytes and microglia are known to play a THE ROLE OF GLIA IN NEUROINFLAMMATION role in the development, spread, and potentiation of neuro- pathic pain (4-12). The role of microglia in initiating or promoting inflammatory processes in the CNS by facilitating the recruitment of periph- Neuroinflammation eral immune cells has been well documented (25-27). During Neuroinflammation is a normal and necessary process. In the the neuroinflammatory process, microglial cells release proin- acute phase after injury, neuroinflammation is tightly con- flammatory mediators such as cytokines, matrix metal- trolled. In its chronic phase or when directed against normal loproteinases (MMP), reactive oxygen species (ROS), and ni- tissue (in an autoimmune response), neuroinflammation is tric oxide (NO). For a long time, glial cells have been consid- detrimental when it manifests itself as multiple sclerosis (MS), ered to merely support the neuronal environment. However, amyotrophic lateral sclerosis (ALS), various types of dementia, the innovative research in the field of neuroscience has -Huntingtonٗs disease, or other diseases (13-16). A wide range strongly propelled glial cells as new players in neuroinflam of neurodegenerative diseases, including those affecting the mation and neuropathic pain. Neuroinflammation is a charac- CNS, such as Alzheimerٗs disease (AD), Parkinsonٗs disease teristic feature of both acute and chronic CNS disorders and (PD), ALS, and MS, are associated with chronic inflammation is a process that results primarily from the presence of chroni- (17-21). Although inflammation may not be the initiating fac- cally activated glial cells (astrocytes and microglia) in the tor, emerging evidence in animal models suggests that sus- brain, and is a common feature of several neurodegenerative tained inflammatory responses involving microglia and as- conditions. Activated glia release a variety of neuroexcitatory trocytes contribute to disease progression (22). The activation substances that potentiate neurotransmission, especially pro- of perivascular microglia and endothelial cells (lining the ca- inflammatory cytokines. Blocking glial activity may be a novel pillary bed), astrocytes (making up the blood-brain barrier), way of controlling neuropathic pain. Neuroinflammation in- parenchymal microglia and astrocytes by the means of stress- duces a complex and dynamic change in glial cell pheno- es, leads to the subsequent production of cytokines, cellular types. One of the first cell types to respond are microglial adhesion molecules, chemokines, and the expression of sur- cells, which retract their processes and migrate towards the face antigens that enhance a CNS immune cascade. If left un- site of injury, where they release proinflammatory cytokines checked, this neuroimmune activation can lead to the traffick- such as IL-1β, TNF-α, and IL-6 (28-30). ing of leukocytes into the perceived area of injury as a mech- anism for neuroprotection. Therefore, neuroinflammation can THE ROLE OF GLIA IN NEUROPATHIC PAIN be defined as the infiltration of immune cells into the site of injury in response to damage to the peripheral or CNS (23). Neuropathic pain is a debilitating condition that affects mil- lions of individuals worldwide. It is now thought that solely Neuropathic pain considering neuronal activity provides an incomplete under- Neuropathic pain, initiated or caused by primary lesions or standing of the creation and maintenance of chronic neuro- dysfunction in the CNS (brain and spinal cord) or the periph- pathic pain (31). Glia have recently emerged as key contrib- eral nervous system (nerves outside the brain and spinal utors to pathological and chronic pain mechanisms and are 42 IMMUNE NETWORK http://www.ksimm.or.kr Volume 12 Number 2 April 2012 Glia in Neuropathic Pain and Inflammation Mithilesh Kumar Jha, et al. emerging as a new target for drug development (32,33). an important role in pain control under pathological condi- Spinal cord glial activation seems to be a