Do glial cells control pain?

Abstract

Management of chronic pain is a real challenge, and current treatments focusing on blocking neurotransmission in the pain pathway have only resulted in limited success. Activation of glia cells has been widely implicated in neuroinflammation in the central nervous system, leading to neruodegeneration in many disease conditions such as Alzheimer's and multiple sclerosis. The inflammatory mediators released by activated glial cells, such as tumor necrosis factor-α and interleukin-1β can not only cause neurodegeneration in these disease conditions, but also cause abnormal pain by acting on spinal cord dorsal horn neurons in injury conditions. Pain can also be potentiated by growth factors such as BDNF and bFGF that are produced by glia to protect neurons. Thus, glia cells can powerfully control pain when they are activated to produce various pain mediators. We will review accumulating evidence supporting an important role of microglia cells in the spinal cord for pain control under injury conditions (e.g. nerve injury). We will also discuss possible signaling mechanisms in particular MAP kinase pathways that are critical for glia control of pain. Investigating signaling mechanisms in microglia may lead to more effective management of devastating chronic pain.

IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain

“…Growing evidence has revealed several microglial molecules involved in neuropathic pain (5)(6)(7)(8)(9). Although the expression levels or activities of these molecules are up-regulated in activated spinal microglia after nerve injury, they remain at low levels in resting microglia under normal conditions (9).…”

“…Accumulating evidence from diverse animal models of neuropathic pain suggests that neuropathic pain might involve aberrant excitability of the nervous system, notably at the levels of the primary sensory ganglia and the dorsal horn of the spinal cord, resulting from multiple functional and anatomical alterations following peripheral nerve injury (3,4). Although it long was thought that these alterations occur mainly in neurons, emerging lines of evidence show that they also occur in spinal microglia, a group of immune cells (5)(6)(7)(8)(9). After injury to peripheral nerves, microglia in the normal state (traditionally called ''resting'' microglia) in the spinal dorsal horn are converted to an activated state through a series of cellular and molecular changes.…”

“…After injury to peripheral nerves, microglia in the normal state (traditionally called ''resting'' microglia) in the spinal dorsal horn are converted to an activated state through a series of cellular and molecular changes. Activated spinal microglia show hypertrophied soma, thickened and retracted processes, and increased proliferation activity (6,9,10). Furthermore, these microglia induce or enhance expression of various genes including neurotransmitter receptors (11) (e.g., P2X 4 R, a subtype of ATP-gated cation channels (12)) and intracellular signaling kinases (e.g., mitogen-activated protein kinases (13)(14)(15)(16) and Lyn tyrosine kinase (17)).…”

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

“…Intrathecal infusion of BDNF or pegylated BDNF caudal to thoracic spinal cord transection or contusive injury similarly promoted cholinergic axon sprouting, stimulated hindlimb air-stepping, and improved both hindlimb joint movements and Basso, Beattie, and Bresnahan open field locomotor rating scale scores [117,118]. To overcome limitations that would obviate using BDNF clinically, such as weight loss (reviewed in Lebrun et al [119]) and involvement in pain [120], we recently evaluated a monoclonal antibody (29D7) that has high affinity for TrkB, the receptor for BDNF [121]. Intrathecal 29D7 infusion caudal to cervical spinal cord dorsal quadrant lesions induced corticospinal tract axon sprouting rostral to the SCI and improved contralesional forelimb pellet retrieval recovery.…”

Lentiviral vectors for gene transfer into the spinal cord glial cells

“…Indeed, this transcription factor regulates a broad panel of target genes, including those encoding numerous pro-inflammatory cytokines and key proteins involved in inflammatory and immune responses. [35][36][37] We and others 38 have demonstrated its rapid activation in spinal cord glial cells following peripheral nerve injury. The NF-kB transduction pathway has also been implicated in pain hypersensitivity.…”