title: 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.
authors.affiliation: Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, USA Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, USA.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Temugin
authors.initials: T
authors.lastname: Berta
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008959:Models, Neurological; D009457:Neuroglia / Q000166:cytology / Q000502:physiology*; D010146:Pain / Q000473:pathology* / Q000503:physiopathology*; D013116:Spinal Cord / Q000473:pathology* / Q000503:physiopathology*
keywords: ATP receptors; Astrocytes; Chemokines; Cytokines; Human; Microglia; Rodents; Satellite glial cells; Spinal cord