Abstract
Mechanisms underlying central neuropathic pain are poorly understood. Although glial dysfunction has been functionally linked with neuropathic pain, very little is known about modulation of pain by oligodendrocytes. Here we report that genetic ablation of oligodendrocytes rapidly triggers a pattern of sensory changes that closely resemble central neuropathic pain, which are manifest before overt demyelination. Primary oligodendrocyte loss is not associated with autoreactive T- and B-cell infiltration in the spinal cord and neither activation of microglia nor reactive astrogliosis contribute functionally to central pain evoked by ablation of oligodendrocytes. Instead, light and electron microscopic analyses reveal axonal pathology in the spinal dorsal horn and spinothalamic tract concurrent with the induction and maintenance of nociceptive hypersensitivity. These data reveal a role for oligodendrocytes in modulating pain and suggest that perturbation of oligodendrocyte functions that maintain axonal integrity can lead to central neuropathic pain independent of immune contributions.
Highlights
Mechanisms underlying central neuropathic pain are poorly understood
Key stages in nociceptive phenotypes were temporally matched with a thorough characterization of the pathophysiological sequelae of changes that occurred with respect to neuronal and glial function as well as axonal and myelin structure
Studies on genetically induced oligodendrocyte ablation[7,8,9,10,11] have converged on a common set of phenotypic changes, despite small differences pertaining to onset and progression of the phenotype between individual models based upon genes targeted by the diphtheria toxin (DTX)-diphtheria toxin receptor (DTR) system and differences in methodological aspects of the genetic ablation system
Summary
Mechanisms underlying central neuropathic pain are poorly understood. glial dysfunction has been functionally linked with neuropathic pain, very little is known about modulation of pain by oligodendrocytes. Light and electron microscopic analyses reveal axonal pathology in the spinal dorsal horn and spinothalamic tract concurrent with the induction and maintenance of nociceptive hypersensitivity These data reveal a role for oligodendrocytes in modulating pain and suggest that perturbation of oligodendrocyte functions that maintain axonal integrity can lead to central neuropathic pain independent of immune contributions. We use a genetic strategy employing diphtheria toxin (DTX)-diphtheria toxin receptor (DTR) system[6] to ablate oligodendrocytes cell-intrinsically in mice Previous studies using this strategy to ablate oligodendrocytes have conclusively shown that primary oligodendrocyte loss leads to secondary axonal damage in the brain independent of CNS inflammation[7,8,9,10,11]. The data suggest that a loss of oligodendrocyte functions that maintain axonal integrity in the spinal cord can trigger neuropathic pain and present a viable addition to immune dysregulation as a target for therapeutic interventions
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