Glia in pathological pain: A role for fractalkine
Section snippets
Previously understood views of pain
Traditionally, our understanding about neuronal signaling for pain transmission from the body to the central nervous system (CNS) occurs as a series of relay signals that are eventually processed in the brain. These relay signals are thought to serve protective and adaptive roles, with the first synaptic relay, between the first order (sensory) neuron and the second order neuron in the dorsal horn of the spinal cord. Neurons that receive and respond to pain information are primarily located in
Glial modulation of neuronal activity
Glia act to dynamically regulate neuronal synaptic communication (Haydon, 2001), and can lead to pathological pain via the release of a variety of neurotransmitters, neuromodulators (McMahon et al., 2005), proinflammatory cytokines and chemokines (Rostene et al., 2007). Astrocytes are closely associated with neuronal somas, dendrites, and pre- and post-synaptic sites, as well as with other glia (microglia), and their functions are now understood to include active, integrative roles during
Evolving views of pain modulation: glia play a significant role in pathological pain states
Diverse animal models of nerve injury or inflammation, either peripherally or centrally, produce pathological pain states such as thermal hyperalgesia (exaggerated responses to painful heat) and mechanical allodynia (non-painful touch/pressure stimuli that become painful) (Zimmermann, 2001). These models have demonstrated the involvement of spinal cord glia which become activated with the development of pain enhancement. For example, pain produced by chronic constriction injury (CCI), a
Neuron-to-glia signals: neurotransmitters and neuromodulators
While a number of factors released spinal cord neurons and glia are known to sensitize neuron–glial interactions leading to pathological pain, the spinal glial response to trauma at distant locations is not fully understood. What are the neuron-to-glial signals that induce subsequent glial activation after peripheral inflammation or nerve trauma? As reviewed above, glia express functional receptors for many neurotransmitters and are able to respond to these signals (Pocock and Kettenmann, 2007
Neuron-to-glia signals: fractalkine
Neurotransmitters and neuromodulators are not the only substances neurons release that can trigger the activation of glia. Fractalkine is another factor released by neurons of the pain pathway, which has been documented to mediate pathological pain (Clark et al., 2007, Lindia et al., 2005, Milligan et al., 2004, Milligan et al., 2005c, Zhuang et al., 2007). Fractalkine, first discovered as neurotactin (Pan et al., 1997) is a chemokine, a term which refers to a family of over 50 proteins
Toll-like receptor signaling in chemokine-mediated pathological pain
Although fractalkine is responsible for the recruitment of natural killer cells during neurodegenerative conditions in animal models for MS or ALS, as well as mediates pain in animal models for neuropathic pain, other innate immune cells (leukocytes) and lymphocytes (T cells) are characterized to migrate into pain-relevant areas of the spinal cord during neuropathic pain conditions (Cao and Deleo, 2008, Sweitzer et al., 2002). The chemoattractant(s) responsible for spinal cord lymphocyte and
Targeting activated glia with anti-inflammatory cytokines to resolve pathological pain
Given chemokines like fractalkine act to attract cells to the site inflammatory activity, anti-inflammatory factors may dampen such signaling. Spinal anti-inflammatory treatment with interleukin-2 (IL-2), interleukin-4 (IL-4), transforming growth factor-beta (TGF-β) (Schafers and Sommer, 2007), and IL-10 (Moore et al., 2001) may prove beneficial. One approach for achieving sustained suppression of proinflammatory cytokine action is by utilizing gene delivery to the spinal cord. Gene-encoding
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