cGMP-Dependent Protein Kinase in Dorsal Root Ganglion: Relationship with Nitric Oxide Synthase and Nociceptive Neurons

Qian, Yifang; Chao, Daniel S.; Santillano, Daniel R; Cornwell, Trudy L.; Nairn, Angus C.; Greengard, Paul; Lincoln, Thomas M.; Bredt, David S.

doi:10.1523/jneurosci.16-10-03130.1996

Cited by 118 publications

(87 citation statements)

References 57 publications

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“…The signal is transduced via cGMP and cGMP-dependent protein kinases (PKG). The calcium current in chick embryo DRG neuron is suppressed by NO donors and membrane-permeable cGMP analog, (42) and the calcium channel is a substrate of PKG (43). Because calcium current is closely associated with nociception (44), decreased activity of the nNOScGMP pathway may be involved in the genesis of hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

et al. 2003

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Streptozocin (STZ)-induced diabetic rats show hyperalgesia that is partially attributed to altered protein kinase C (PKC) activity. Both attenuated neuronal nitric oxide synthase (nNOS)-cGMP system and tetrodotoxin-resistant (TTX-R) Na channels in dorsal root ganglion neurons may be involved in diabetic hyperalgesia. We examined whether PKC␤ inhibition ameliorates diabetic hyperalgesia and, if so, whether the effect is obtained through action on neurons by testing nociceptive threshold in normal and STZ-induced diabetic rats treated with or without PKC␤-selective inhibitor LY333531 (LY) and by assessing the implication of LY in either nNOS-cGMP system or TTX-R Na channels of isolated dorsal root ganglion neurons. The decreased nociceptive threshold in diabetic rats was improved either after 4 weeks of LY treatment or with a single intradermal injection into the footpads. The treatment of LY for 6 weeks significantly decreased p-PKC␤ and ameliorated a decrease in cGMP content in dorsal root ganglia of diabetic rats. The latter effect was confirmed in ex vivo condition. The treatment with NO donor for 4 weeks also normalized both diabetic hyperalgesia and decreased cGMP content in dorsal root ganglions. The expressions of nNOS and TTX-R Na channels were not changed with LY treatment. These results suggest that LY is effective for treating diabetic hyperalgesia through ameliorating the decrease in the nNOS-cGMP system.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

et al. 2003

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“…A major target of cGMP in nociceptive processing is cGMP-dependent protein kinase I (cGKI, also known as PKG-I), of which the ␣-isoform is expressed in smalland medium-diameter dorsal root ganglion (DRG) neurons and in superficial laminas of the spinal cord (Qian et al, 1996;. The expression of cGKI in the spinal cord is upregulated after noxious stimulation, and intrathecal administration of cGKI inhibitors provided profound antinociceptive effects in various animal models of pain Schmidtko et al, 2003;Song et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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

Schmidtko¹,

Gao²,

Sausbier³

et al. 2008

J. Neurosci.

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The cGMP/cGMP-dependent protein kinase I (cGKI) signaling pathway plays an important role in spinal nociceptive processing. However, downstream targets of cGKI in this context have not been identified to date. Using a yeast two-hybrid screen, we isolated cysteinerich protein 2 (CRP2) as a novel cGKI interactor in the spinal cord. CRP2 is expressed in laminas I and II of the mouse spinal cord and is colocalized with cGKI, calcitonin gene-related peptide, and isolectin B4. Moreover, the majority of CRP2 mRNA-positive dorsal root ganglion (DRG) neurons express cGKI and peripherin. CRP2 is phosphorylated in a cGMP-dependent manner, and its expression increases in the spinal cord and in DRGs after noxious stimulation of a hindpaw. To elucidate the functional role of CRP2 in nociception, we analyzed mice with a targeted deletion of CRP2. CRP2-deficient (CRP2 Ϫ/Ϫ ) mice demonstrate normal behavioral responses to acute nociception and after axonal injury of the sciatic nerve, but increased nociceptive behavior in models of inflammatory hyperalgesia compared with wild-type mice. Intrathecal administration of cGMP analogs increases the nociceptive behavior in wild-type but not in CRP2 Ϫ/Ϫ mice, indicating that the presence of CRP2 is important for cGMP-mediated nociception. These data suggest that CRP2 is a new downstream effector of cGKI-mediated spinal nociceptive processing and point to an inhibitory role of CRP2 in the generation of inflammatory pain.

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“…T he second messenger cGMP is formed by activation of soluble and particulate guanylyl cyclases and has several targets, including cGMP-dependent protein kinase I (PKG-I) and PKG-II, of which PKG-I is expressed in the spinal cord (1,2). Spinally delivered PKG inhibitors reduce formalin-induced nociceptive behavior in rats (3,4), suggesting that PKG-I plays an important role in spinal nociceptive processing.…”

mentioning

confidence: 99%

Reduced inflammatory hyperalgesia with preservation of acute thermal nociception in mice lacking cGMP-dependent protein kinase I

Tegeder

Turco²,

Schmidtko³

et al. 2004

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

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cGMP-dependent protein kinase I (PKG-I) has been suggested to contribute to the facilitation of nociceptive transmission in the spinal cord presumably by acting as a downstream target of nitric oxide. However, PKG-I activators caused conflicting effects on nociceptive behavior. In the present study we used PKG-I ؊/؊ mice to further assess the role of PKG-I in nociception. PKG-I deficiency was associated with reduced nociceptive behavior in the formalin assay and zymosan-induced paw inflammation. However, acute thermal nociception in the hot-plate test was unaltered. After spinal delivery of the PKG inhibitor, Rp-8-Br-cGMPS, nociceptive behavior of PKG-I ؉/؉ mice was indistinguishable from that of PKG-I ؊/؊ mice. On the other hand, the PKG activator, 8-Br-cGMP (250 nmol intrathecally) caused mechanical allodynia only in PKG-I ؉/؉ mice, indicating that the presence of PKG-I was essential for this effect. Immunofluorescence studies of the spinal cord revealed additional morphological differences. In the dorsal horn of 3-to 4-week-old PKG-I ؊/؊ mice laminae I-III were smaller and contained fewer neurons than controls. Furthermore, the density of substance P-positive neurons and fibers was significantly reduced. The paucity of substance P in laminae I-III may contribute to the reduction of nociception in PKG-I ؊/؊ mice and suggests a role of PKG-I in substance P synthesis.spinal cord ͉ substance P ͉ nitric oxide ͉ pain T he second messenger cGMP is formed by activation of soluble and particulate guanylyl cyclases and has several targets, including cGMP-dependent protein kinase I (PKG-I) and PKG-II, of which PKG-I is expressed in the spinal cord (1, 2). Spinally delivered PKG inhibitors reduce formalin-induced nociceptive behavior in rats (3, 4), suggesting that PKG-I plays an important role in spinal nociceptive processing. It has been speculated that PKG-I mediates hyperalgesic effects of nitric oxide (NO) (5). This idea is supported by the observation that PKG-I inhibition causes a reduction of thermal hyperalgesia induced by injection of the NO donor, NOC-12 (6). Endogenous NO is produced by NO synthases, of which neuronal nitric oxide synthase (nNOS) is activated and up-regulated after N-methyl-D-aspartate receptor stimulation (7-10). NO probably acts as a retrograde messenger (11, 12) at nociceptive synapses, i.e., it is released from the postsynaptic neuron, diffuses back to the presynaptic neuron, and stimulates guanylyl cyclases. The latter step links NO to cGMP production and PKG-I activation. Because inhibition of NOS activity reduces nociception (13,14), the release of NO is thought to contribute to the development of hyperexcitability of nociceptive neurons under certain circumstances. Under the premise that PKG-I is a mediator of NO at nociceptive synapses, one would expect that PKG-I activation also causes hyperalgesia. However, effects of the spinally delivered PKG activator 8-Br-cGMP have been conflicting (15,16). (See Supporting Text, which is published as supporting information on the PNAS web site....

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cGMP-Dependent Protein Kinase in Dorsal Root Ganglion: Relationship with Nitric Oxide Synthase and Nociceptive Neurons

Cited by 118 publications

References 57 publications

Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

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

Reduced inflammatory hyperalgesia with preservation of acute thermal nociception in mice lacking cGMP-dependent protein kinase I

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