Involvement of phosphorylated Ca2+/calmodulin-dependent protein kinase II and phosphorylated extracellular signal-regulated protein in the mouse formalin pain model

Choi, Seong-Soo; Seo, Young-Jun; Shim, Eon-Jeong; Kwon, Min-Soo; Lee, Jin Young; Ham, Young-Ok; Suh, Hong‐Won

doi:10.1016/j.brainres.2006.06.048

Cited by 55 publications

(43 citation statements)

References 52 publications

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“…Here we monitored the formalininduced phosphorylation of the Ca 2ϩ /calmodulin-regulated kinase II (CamKII) on threonine 286. As described previously (42), formalin injection in the hind paws induced an increased phosphorylation of CamKII in the outer laminae of the dorsal horn (Fig. 6, C and D).…”

Section: Dihydro-s1p Inhibits the Campdependent Phosphorylation Of Nmsupporting

confidence: 79%

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Coste

Brenneis

Linke

et al. 2008

Journal of Biological Chemistry

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Sphingosine 1-Phosphate (S1P) modulates various cellular functions such as apoptosis, cell differentiation, and migration. Although S1P is an abundant signaling molecule in the central nervous system, very little is known about its influence on neuronal functions. We found that S1P concentrations were selectively decreased in the cerebrospinal fluid of adult rats in an acute and an inflammatory pain model. Pharmacological inhibition of sphingosine kinases (SPHK) decreased basal pain thresholds and SphK2 knock-out mice, but not SphK1 knock-out mice, had a significant decrease in withdrawal latency. Intrathecal application of S1P or sphinganine 1-phosphate (dihydro-S1P) reduced the pain-related (nociceptive) behavior in the formalin assay. S1P and dihydro-S1P inhibited cyclic AMP (cAMP) synthesis, a key second messenger of spinal nociceptive processing, in spinal cord neurons. By combining fluorescence resonance energy transfer (FRET)-based cAMP measurements with Multi Epitope Ligand Cartography (MELC), we showed that S1P decreased cAMP synthesis in excitatory dorsal horn neurons. Accordingly, intrathecal application of dihydro-S1P abolished the cAMP-dependent phosphorylation of NMDA receptors in the outer laminae of the spinal cord. Taken together, the data show that S1P modulates spinal nociceptive processing through inhibition of neuronal cAMP synthesis.The bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P) 2 is synthesized by phosphorylation of sphingosine by sphingosine kinases (SPHK) in a wide variety of cell types in response to extracellular stimuli such as nerve growth factor or vascular endothelial growth factor. S1P modulates diverse cellular functions such as apoptosis, cell differentiation, and migration either through the activation of a family of five G-protein-coupled receptors (S1P 1-5 ) or by acting as an intracellular second messenger (1-3). In the central nervous system S1P has been shown to be released by cerebellar granule cells and astrocytes (4 -6). Regarding its function in the central nervous system it is well known that S1P promotes survival of neurons and astrocytes, induces proliferation of neural progenitor cells and astrocytes, and mediates nerve growth factor (NGF)-stimulated neurite outgrowth (2, 3, 7). However, very little is known about the role of S1P in the regulation of neuronal excitability and the mechanisms that mediate these S1P functions. Recently whole cell patch clamp recordings revealed that loss of S1P 2 leads to a large increase in the excitability of neocortical pyramidal neurons (8), suggesting an inhibitory effect of S1P 2 on neuronal excitability. On the other hand, several in vitro studies show that S1P can also increase neuronal functions. For example, S1P receptor activation augments glutamate secretion in hippocampal neurons (9) and elevated intracellular S1P concentrations enhance the spontaneous neurotransmitter release at neuromuscular junctions (10). Furthermore, intra-as well as extracellularly applied S1P facilitated the NGF-induced increas...

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Section: Dihydro-s1p Inhibits the Campdependent Phosphorylation Of Nmsupporting

confidence: 79%

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Coste

Brenneis

Linke

et al. 2008

Journal of Biological Chemistry

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“…In the formalin inflammation model, the second phase of formalin-induced paw-licking behavior was significantly reduced by KN93 (Choi et al, 2006) and largely absent in CaMKII␣(T286A) mutant mice (Zeitz et al, 2004). We found that KN93, but not its inactive analog KN92, prevented or reversed CFA-induced mechanical allodynia and thermal hyperalgesia (Luo et al, 2008).…”

Section: Discussionmentioning

confidence: 70%

Acute Inhibition of Ca²⁺/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice

Chen

Luo

Yang

et al. 2009

J Pharmacol Exp Ther

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The limited data that currently exist for the role of Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) in neuropathic pain are conflicting. In the present study, we tested the hypothesis that CaMKII is required for the maintenance of neuropathic pain in a rodent model of experimental mononeuropathy. Spinal nerve L 5 /L 6 ligation (SNL) was found to increase the spinal activity of CaMKII (pCaMKII) on the ipsilateral (but not contralateral) side. This effect was blocked by 2-[N-(2-hydroxyethyl)-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-Nmethylbenzylamine) (KN93) (intrathecal injection), a CaMKII inhibitor. Acute treatment with KN93 dose-dependently reversed SNL-induced thermal hyperalgesia and mechanical allodynia. The action of KN93 lasted for at least 2 to 4 h. 2-[N-(4-Methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-Nmethylbenzylamine (KN92) (45 nmol i.t.), an inactive analog of KN93, showed no effect on SNL-induced CaMKII activation, allodynia, or hyperalgesia. We further examined the pharmacologic action of trifluoperazine, a clinically used antipsychotic drug that we found to be a potent CaMKII inhibitor in these assays. Trifluoperazine (administered intraperitoneally or by mouth) dose-dependently reversed SNL-induced mechanical allodynia, thermal hyperalgesia, and CaMKII activation without causing locomotor impairment in mice at the highest doses used. In conclusion, our findings support a critical role of CaMKII in neuropathic pain. Blocking CaMKII or CaMKII-mediated signaling may offer a novel therapeutic target for the treatment of neuropathic pain.

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“…Recent studies with several animal pain models have suggested a crucial role of CaMKII in persistent pain and the change of CaMKII activity or expression in these models have been described, such as complete Freund's adjuvant induced chronic inflammatory pain [20], formalin subcutaneous induced inflammation model [4], diabetic neuropathic pain [7,8,12], spinal nerve ligation pain [3], spinal contusion injury [5], spared nerve injury model [13], partial sciatic nerve ligation neuropathic pain [26] and oxaliplatin induced neuropathy [24]. And inhibiting the activity of CaMKII could attenuate pain-related behavior.…”

Section: Introductionmentioning

confidence: 99%

Intra-nucleus accumbens administration of the calcium/calmodulin-dependent protein kinase II inhibitor KN93 induced antinociception in rats with mononeuropathy

Bian

2014

Neuroscience Letters

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The present study was conducted on rats with mononeuropathy induced by left common sciatic nerve ligation. Unilateral sciatic nerve loose ligation produced decreases of the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation. Intra-nucleus accumbens (NAc) injection of 1μg, 3μg and 6μg of KN93, the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor, dose-dependently increased the HWL in mononeuropathic rats. Furthermore, intra-NAc administration of morphine, the HWL to noxious thermal and mechanical stimulation increased markedly, and there were no significant differences between morphine group and KN93 group. The results demonstrated that intra-NAc injection of KN93 induced significant antinociceptive effects in rats with mononeuropathy, indicating CaMKII may play important roles in transmission of nociceptive information in the NAc of mononeuropathic rats.

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Involvement of phosphorylated Ca2+/calmodulin-dependent protein kinase II and phosphorylated extracellular signal-regulated protein in the mouse formalin pain model

Cited by 55 publications

References 52 publications

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Acute Inhibition of Ca²⁺/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice

Intra-nucleus accumbens administration of the calcium/calmodulin-dependent protein kinase II inhibitor KN93 induced antinociception in rats with mononeuropathy

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Involvement of phosphorylated Ca2+/calmodulin-dependent protein kinase II and phosphorylated extracellular signal-regulated protein in the mouse formalin pain model

Cited by 55 publications

References 52 publications

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Acute Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice

Intra-nucleus accumbens administration of the calcium/calmodulin-dependent protein kinase II inhibitor KN93 induced antinociception in rats with mononeuropathy

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Acute Inhibition of Ca²⁺/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice