Cysteine-Rich Protein 2, a Novel Downstream Effector of cGMP/cGMP-Dependent Protein Kinase I-Mediated Persistent Inflammatory Pain

Schmidtko, Achim; Gao, Wei; Sausbier, Matthias; Rauhmeier, Inga; Sausbier, Ulrike; Niederberger, Ellen; Scholich, Klaus; Huber, Andrea; Neuhuber, Winfried; Allescher, Hans–Dieter; Hofmann, Franz; Tegeder, Irmgard; Ruth, Peter; Geißlinger, Gerd

doi:10.1523/jneurosci.5037-07.2008

Cited by 58 publications

(61 citation statements)

References 48 publications

(67 reference statements)

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“…For staining with Griffonia simplicifolia isolectin B4 (IB4), sections were incubated with Alexa Fluor 488-conjugated IB4 (10 g/ml in PBS; Invitrogen) for 2 h at room temperature. After immunostaining, slides were immersed for 5 min in 0.06% Sudan black B (in 70% ethanol) to reduce lipofuscin-like autofluorescence (Schnell et al, 1999;Schmidtko et al, 2008c), washed in PBS, and coverslipped. In double-labeling experiments, primary antibodies were consecutively incubated.…”

Section: Immunostainingmentioning

confidence: 99%

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

Kallenborn-Gerhardt¹,

Schröder²,

Turco³

et al. 2012

Journal of Neuroscience

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Reactive oxygen species (ROS) contribute to sensitization of pain pathways during neuropathic pain, but little is known about the primary sources of ROS production and how ROS mediate pain sensitization. Here, we show that the NADPH oxidase isoform Nox4, a major ROS source in somatic cells, is expressed in a subset of nonpeptidergic nociceptors and myelinated dorsal root ganglia neurons. Mice lacking Nox4 demonstrated a substantially reduced late-phase neuropathic pain behavior after peripheral nerve injury. The loss of Nox4 markedly attenuated injury-induced ROS production and dysmyelination processes of peripheral nerves. Moreover, persisting neuropathic pain behavior was inhibited after tamoxifen-induced deletion of Nox4 in adult transgenic mice. Our results suggest that Nox4 essentially contributes to nociceptive processing in neuropathic pain states. Accordingly, inhibition of Nox4 may provide a novel therapeutic modality for the treatment of neuropathic pain.

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Section: Immunostainingmentioning

confidence: 99%

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

Kallenborn-Gerhardt¹,

Schröder²,

Turco³

et al. 2012

Journal of Neuroscience

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“…Inhibition of NO synthesis in the spinal cord reduces inflammatory and neuropathic pain, suggesting an overall pronociceptive effect of NO (Meller et al, 1992;Malmberg and Yaksh1993). Spinal application of NO donors or cGMP analogs revealed conflicting results as pronociceptive and antinociceptive effects have been observed (Sousa and Prado, 2001;Tegeder et al, 2002;Schmidtko et al, 2008). The effect of NO on the spontaneous activity of spinal neurons varies with respect to the lamina location.…”

Section: Ltp Gaba In the Superficial Dorsal Horn Is Heterosynaptic Inmentioning

confidence: 99%

Heterosynaptic Long-Term Potentiation at GABAergic Synapses of Spinal Lamina I Neurons

Fenselau¹,

Heinke²,

Sandkühler³

2011

J. Neurosci.

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Neurons in spinal dorsal horn lamina I play a pivotal role for nociception that critically depends on a proper balance between excitatory and inhibitory inputs. Any modification in synaptic strength may challenge this delicate balance. Long-term potentiation (LTP) at glutamatergic synapses between nociceptive C-fibers and lamina I neurons is an intensively studied cellular model of pain amplification. In contrast, nothing is presently known about long-term changes of synaptic strength at inhibitory synapses in the spinal dorsal horn. Using a spinal cord-dorsal root slice preparation from rats, we show that conditioning stimulation of primary afferent fibers with a stimulating protocol that induces LTP at C-fiber synapses also triggered LTP at GABAergic synapses (LTP GABA ). This LTP GABA was heterosynaptic in nature and was mediated by activation of group I metabotropic glutamate receptors. Opening of ionotropic glutamate receptor channels of the AMPA/KA or NMDA subtype was not required for LTP GABA . Paired-pulse ratio, coefficient of variation, and miniature IPSCs analysis revealed that LTP GABA was expressed presynaptically. Nitric oxide as a retrograde messenger signal mediated this increase of GABA release at spinal inhibitory synapses. This novel form of synaptic plasticity in spinal nociceptive circuits may be an essential mechanism to maintain the relative balance between excitation and inhibition and to improve the signal-to-noise ratio in nociceptive pathways.

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“…In fact, several studies revealed that NO donors and cGMP analogs, in addition to their well characterized pronociceptive effects, may also inhibit pain (Iwamoto and Marion, 1994;Pehl and Schmid, 1997;Tegeder et al, 2002Tegeder et al, , 2004Schmidtko et al, 2008b). Interestingly, the antinociceptive effects of cGMP analogs were not antagonized by coadministration with a cGKI inhibitor and were also observed in cGKI Ϫ/Ϫ mice, suggesting that cGKI-independent mechanisms are involved.…”

Section: Discussionmentioning

confidence: 99%

“…For intrathecal drug delivery, a catheter was implanted onto the lumbosacral spinal cord (L4 -L5) as described previously (Schmidtko et al, 2008b). The mechanical sensitivity of both hindpaws was assessed using the dynamic-plantar test.…”

Section: Behavioral Testingmentioning

confidence: 99%

“…The contribution of cGKI to pain sensitization is reflected by the reduced inflammatory hyperalgesia in cGKI Ϫ/Ϫ mice (Tegeder et al, 2004), and by antinociceptive effects of cGKI inhibitors (Tao et al, 2000;Schmidtko et al, 2003). However, there is accumulating evidence that cGMP may also exert antinociceptive effects within the spinal cord independently from cGKI activation (Iwamoto and Marion, 1994;Tegeder et al, 2002Tegeder et al, , 2004Schmidtko et al, 2008b). This indicates that, in addition to cGKI, other cGMP targets might be involved in nociceptive signaling.…”

Section: Introductionmentioning

confidence: 99%

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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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Cysteine-Rich Protein 2, a Novel Downstream Effector of cGMP/cGMP-Dependent Protein Kinase I-Mediated Persistent Inflammatory Pain

Cited by 58 publications

References 48 publications

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

Heterosynaptic Long-Term Potentiation at GABAergic Synapses of Spinal Lamina I Neurons

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

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