Induction of Thermal Hyperalgesia and Synaptic Long-Term Potentiation in the Spinal Cord Lamina I by TNF-α and IL-1β is Mediated by Glial Cells

Gruber‐Schoffnegger, Doris; Drdla-Schutting, Ruth; Hönigsperger, Christoph; Wunderbaldinger, Gabriele; Gassner, Matthias; Sandkühler, Jürgen

doi:10.1523/jneurosci.5087-12.2013

Cited by 189 publications

(208 citation statements)

References 72 publications

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“…The time course of GlyR LTP requires instead a rapid signaling pathway likely to involve p38 MAPK, a kinase strongly implicated in pain processing in the dorsal horn, and which rapidly enhances voltage-gated sodium currents in nociceptors in response to IL-1β (31). Although our data cannot rule out the possibility that IL-1β releases another signaling molecule that itself up-regulates glycine receptors in neurons, as suggested for excitatory dorsal horn synaptic potentiation (38), the rapid time course of GlyR LTP makes this less likely. IL-1β can modulate synaptic currents in unidentified superficial dorsal horn neurons, transiently increasing (64) or decreasing IPSC amplitudes (35), and synaptic potentiation of excitatory C-fiber synapses on lamina I neurons requires the release of IL-1β (38) during peripheral inflammation.…”

Section: Glycine Receptor Trafficking and Channel Properties Modulatementioning

confidence: 63%

“…Blocking glycine receptor LTP may represent a useful therapeutic strategy in the treatment of inflammatory pain. molecules released from glial cells (38). Here we report that IL-1β rapidly elicits a postsynaptic form of long-term potentiation (LTP) at glycinergic synapses on lamina II inhibitory neurons (GlyR LTP), and that the same glycinergic synapses are potentiated after peripheral inflammation.…”

Section: Significancementioning

confidence: 98%

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Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Chirila

Brown

Bishop

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Long-term potentiation (LTP) is a persistent increase in synaptic strength required for many behavioral adaptations, including learning and memory, visual and somatosensory system functional development, and drug addiction. Recent work has suggested a role for LTP-like phenomena in the processing of nociceptive information in the dorsal horn and in the generation of central sensitization during chronic pain states. Whereas LTP of glutamatergic and GABAergic synapses has been characterized throughout the central nervous system, to our knowledge there have been no reports of LTP at mammalian glycinergic synapses. Glycine receptors (GlyRs) are structurally related to GABA A receptors and have a similar inhibitory role. Here we report that in the superficial dorsal horn of the spinal cord, glycinergic synapses on inhibitory GABAergic neurons exhibit LTP, occurring rapidly after exposure to the inflammatory cytokine interleukin-1 beta. This form of LTP (GlyR LTP) results from an increase in the number and/or change in biophysical properties of postsynaptic glycine receptors. Notably, formalin-induced peripheral inflammation in vivo potentiates glycinergic synapses on dorsal horn neurons, suggesting that GlyR LTP is triggered during inflammatory peripheral injury. Our results define a previously unidentified mechanism that could disinhibit neurons transmitting nociceptive information and may represent a useful therapeutic target for the treatment of pain.G lycine mediates fast synaptic inhibition throughout the spinal cord, brainstem, and midbrain, controlling normal motor behavior and rhythm generation, somatosensory processing, auditory and retinal signaling, and coordination of reflex responses (1). Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels of the Cys-loop receptor family that together with GABA A receptors (GABA A Rs) dynamically interact with the synaptic scaffold protein gephyrin to form inhibitory synapses (1, 2). In the dorsal horn of the spinal cord, glycinergic synapses are essential for nociceptive and tactile sensory processing both during adaptive and pathological pain states (3-7). However, compared with glutamatergic and GABAergic synapses, little is known about the regulation of their synaptic strength. Several studies have examined glycine receptor trafficking in cultured neurons and in heterologous expression systems (8, 9). Intracellular Ca 2+ appears important in the stabilization of GlyRs at synapses in culture (10), and elevation of intracellular Ca 2+ can also potently increase glycine receptor single channel openings in cultured cells and in heterologous systems (11). However, the modulation of glycinergic synaptic strength in native tissue remains relatively unexplored.Following peripheral injury or inflammation, changes in tactile perception develop, including hyperalgesia (exaggerated pain upon noxious stimulation), allodynia (pain in response to innocuous stimuli), and secondary hyperalgesia (pain spreading beyond the confines of the injure...

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Section: Glycine Receptor Trafficking and Channel Properties Modulatementioning

confidence: 63%

Section: Significancementioning

confidence: 98%

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Chirila

Brown

Bishop

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…TNF-α also may regulate inhibitory synaptic transmission in the spinal cord via disinhibition (49). TNF-α is required for the induction of spinal LTP and inflammatory pain (43,50,51). In addition to direct modulation of synaptic transmission, TNF-α further stimulates glial cells to release proinflammatory mediators to enhance synaptic transmission and LTP (50).…”

Section: Methodsmentioning

confidence: 99%

“…TNF-α is required for the induction of spinal LTP and inflammatory pain (43,50,51). In addition to direct modulation of synaptic transmission, TNF-α further stimulates glial cells to release proinflammatory mediators to enhance synaptic transmission and LTP (50). Endogenous CASP6 and TNF-α have effects similar to those of exogenous CASP6 and TNF-α on synaptic transmission and inflammation pain.…”

Section: Methodsmentioning

confidence: 99%

“…Endogenous CASP6 and TNF-α have effects similar to those of exogenous CASP6 and TNF-α on synaptic transmission and inflammation pain. Thus, spinal LTP and inflammatory pain are abrogated after deletion of Casp6 or Tnfr and inhibition of CASP6 and TNF-α (38,43,50), and inflammation-induced spinal synaptic plasticity (sEPSC increase) also was impaired by CASP6 inhibition and deletion.…”

Section: Methodsmentioning

confidence: 99%

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Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

et al. 2014

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Increasing evidence indicates that the pathogenesis of neuropathic pain is mediated through spinal cord microglia activation. The intracellular protease caspase-6 (CASP6) is known to regulate neuronal apoptosis and axonal degeneration; however, the contribution of microglia and CASP6 in modulating synaptic transmission and pain is unclear. Here, we found that CASP6 is expressed specifically in C-fiber axonal terminals in the superficial spinal cord dorsal horn. Animals exposed to intraplantar formalin or bradykinin injection exhibited CASP6 activation in the dorsal horn. Casp6-null mice had normal baseline pain, but impaired inflammatory pain responses. Furthermore, formalin-induced second-phase pain was suppressed by spinal injection of CASP6 inhibitor or CASP6-neutralizing antibody, as well as perisciatic nerve injection of CASP6 siRNA. Recombinant CASP6 (rCASP6) induced marked TNF-α release in microglial cultures, and most microglia within the spinal cord expressed Tnfa. Spinal injection of rCASP6 elicited TNF-α production and microgliadependent pain hypersensitivity. Evaluation of excitatory postsynaptic currents (EPSCs) revealed that rCASP6 rapidly increased synaptic transmission in spinal cord slices via TNF-α release. Interestingly, the microglial inhibitor minocycline suppressed rCASP6 but not TNF-α−induced synaptic potentiation. Finally, rCASP6-activated microglial culture medium increased EPSCs in spinal cord slices via TNF-α. Together, these data suggest that CASP6 released from axonal terminals regulates microglial TNF-α secretion, synaptic plasticity, and inflammatory pain.

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Spinal plasticity of the nociceptive system

Latrémolière

2016

An Introduction to Pain and Its Relation to Nervous System Disorders

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Induction of Thermal Hyperalgesia and Synaptic Long-Term Potentiation in the Spinal Cord Lamina I by TNF-α and IL-1β is Mediated by Glial Cells

Cited by 189 publications

References 72 publications

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

Spinal plasticity of the nociceptive system

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