Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control

Zeilhofer, Hanns Ulrich; Wildner, Hendrik; Yévenes, Gonzalo E.

doi:10.1152/physrev.00043.2010

Cited by 327 publications

(327 citation statements)

References 421 publications

(584 reference statements)

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“…There has been considerable interest in the idea that the removal of GABAergic/glycinergic inhibition contributes to nociception and central sensitization resulting from inflammation, peripheral nerve damage, or experimental C-fiber excitation (2,3,6,12,21). Dorsal horn functional circuitry is incompletely mapped out, but lamina II GABAergic interneurons are ideally located to gate the flow of nociceptive information from the periphery to supraspinal areas.…”

Section: Glycine Receptor Trafficking and Channel Properties Modulatementioning

confidence: 99%

“…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)(4)(5)(6)(7).…”

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confidence: 99%

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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: 99%

mentioning

confidence: 99%

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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“…In neuropathic pain states, tonic GABA inhibition is suppressed in superficial dorsal horn nociceptive neurons and enhanced excitatory signaling is no longer regulated by inhibitory controls, leading to a net neuronal hyperexcitability (Zeilhofer et al, 2012). Loss of GABA inhibition can result from a number of pathophysiological changes in key components throughout the GABA system.…”

Section: Introductionmentioning

confidence: 99%

Engagement of the GABA to KCC2 Signaling Pathway Contributes to the Analgesic Effects of A₃AR Agonists in Neuropathic Pain

et al. 2015

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More than 1.5 billion people worldwide suffer from chronic pain, yet current treatment strategies often lack efficacy or have deleterious side effects in patients. Adenosine is an inhibitory neuromodulator that was previously thought to mediate antinociception through the A 1 and A 2A receptor subtypes. We have since demonstrated that A 3 AR agonists have potent analgesic actions in preclinical rodent models of neuropathic pain and that A 3 AR analgesia is independent of adenosine A 1 or A 2A unwanted effects. Herein, we explored the contribution of the GABA inhibitory system to A 3 AR-mediated analgesia using well-characterized mouse and rat models of chronic constriction injury (CCI)-induced neuropathic pain. The deregulation of GABA signaling in pathophysiological pain states is well established: GABA signaling can be hampered by a reduction in extracellular GABA synthesis by GAD65 and enhanced extracellular GABA reuptake via the GABA transporter, GAT-1. In neuropathic pain, GABA A R-mediated signaling can be further disrupted by the loss of the KCC2 chloride anion gradient. Here, we demonstrate that A 3 AR agonists (IB-MECA and MRS5698) reverse neuropathic pain via a spinal mechanism of action that modulates GABA activity. Spinal administration of the GABA A antagonist, bicuculline, disrupted A 3 AR-mediated analgesia. Furthermore, A 3 AR-mediated analgesia was associated with reductions in CCI-related GAD65 and GAT-1 serine dephosphorylation as well as an enhancement of KCC2 serine phosphorylation and activity. Our results suggest that A 3 AR-mediated reversal of neuropathic pain increases modulation of GABA inhibitory neurotransmission both directly and indirectly through protection of KCC2 function, underscoring the unique utility of A 3 AR agonists in chronic pain.

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“…Glycine is an inhibitory neurotransmitter in the spinal cord and brain stem where it binds and activates glycine receptors (GlyRs) to cause hyperpolarization [2,3]. Glycine is also an excitatory neurotransmitter throughout the CNS where it acts as a co-agonist with glutamate at the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors to cause depolarization [4].…”

Section: Glycine Neurotransmission and Chronic Painmentioning

confidence: 99%