Synaptic Amplifier of Inflammatory Pain in the Spinal Dorsal Horn

Ikeda, Hiroshi; Stark, J.; Fischer, H.; Wagner, Matthias; Drdla, Ruth; Jäger, Tino; Sandkühler, Jürgen

doi:10.1126/science.1127233

Cited by 415 publications

(443 citation statements)

References 26 publications

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“…Several lines of evidence indicate that cGMP can exert pronociceptive effects in NK1-R-positive lamina I projection neurons. In particular, previous studies revealed that long-term potentiation of synapses between C-fibers and lamina I projection neurons is NO dependent (Ikeda et al, 2006), and that selective ablation of these neurons considerably attenuated inflammatory and neuropathic pain (Mantyh et al, 1997;Nichols et al, 1999;Khasabov et al, 2002). However, our data indicate that cGMP produced by NO-GC in inhibitory neurons exerts antinociceptive effects that are mediated by CNGA3.…”

Section: Discussioncontrasting

confidence: 54%

CNGA3: A Target of Spinal Nitric Oxide/cGMP Signaling and Modulator of Inflammatory Pain Hypersensitivity

Heine

Michalakis²,

Kallenborn-Gerhardt³

et al. 2011

J. Neurosci.

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A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing. In situ hybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3 Ϫ/Ϫ mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover, CNGA3 Ϫ/Ϫ mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling.

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Section: Discussioncontrasting

confidence: 54%

CNGA3: A Target of Spinal Nitric Oxide/cGMP Signaling and Modulator of Inflammatory Pain Hypersensitivity

Heine

Michalakis²,

Kallenborn-Gerhardt³

et al. 2011

J. Neurosci.

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“…LTP at glutamatergic C-fiber synapses onto lamina I projection neurons has been extensively studied as a cellular mechanism accompanying hyperalgesia (18,(46)(47)(48), but relatively little is known about plasticity at dorsal horn inhibitory synapses (49). To our knowledge, the LTP we describe here is the first example of LTP at glycinergic synapses in the mammalian CNS.…”

Section: Discussionmentioning

confidence: 81%

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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“…However, when these receptors are exposed to μ-opioid receptor agonists, such as remifentanil, this connection can be broken. This causes an increase in the sensitivity of NMDARs to glutamate and glycine, leading to membrane depolarization (Ikeda et al, 2006). The activated NMDARs then allow Ca 2+ to enter into neurons.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of the GluN1 subunit in dorsal horn neurons by remifentanil: a mechanism for opioid-induced hyperalgesia

C¹,

Li²,

Zhao³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Remifentanil (an ultra-short acting μ-opioid receptor agonist) use has been associated with acute opioid tolerance and hyperalgesia. Previous electrophysiological studies have shown that remifentanil elicits rapid and prolonged upregulation of N-methyl-D-aspartate receptor (NMDAR) currents. However, the effect of remifentanil on the levels of the GluN1 subunit of the NMDAR in dorsal horn neurons (DHNs) has not been reported. We investigated the effect of remifentanil, along with ketamine (NMDAR antagonist) and naloxone (μ-opioid receptor antagonist), on GluN1 mRNA levels and the amount of phosphorylated GluN1 in primary cultures of embryonic rat DHNs. DHNs were isolated from 18-19-day rat embryos and treated with remifentanil or vehicle for 1 h. GluN1 mRNA and protein levels, determined by real time reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively, were significantly and persistently increased by remifentanil exposure compared with the control group (P ＜ 0.05). These results may partially account for the 1847 Phosphorylation of GluN1 by remifentanil ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (1): 1846-1854(2015 mechanism of remifentanil-induced hyperalgesia. This increase was prevented by ketamine (NMDAR antagonist) and naloxone (μ-opioid receptors antagonist), thus providing a potential therapeutic mechanism for the prevention of opioid-induced hyperalgesia.

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Synaptic Amplifier of Inflammatory Pain in the Spinal Dorsal Horn

Cited by 415 publications

References 26 publications

CNGA3: A Target of Spinal Nitric Oxide/cGMP Signaling and Modulator of Inflammatory Pain Hypersensitivity

CNGA3: A Target of Spinal Nitric Oxide/cGMP Signaling and Modulator of Inflammatory Pain Hypersensitivity

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

Phosphorylation of the GluN1 subunit in dorsal horn neurons by remifentanil: a mechanism for opioid-induced hyperalgesia

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