In Vivo Activity of a Phospholipase C Inhibitor, 1-(6-((17β-3-Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1<i>H</i>-pyrrole-2,5-dione (U73122), in Acute and Chronic Inflammatory Reactions

Hou, Cuifen; Kirchner, Thomas; Singer, Monica; Matheis, Michele; Argentieri, Dennis; Cavender, Druie

doi:10.1124/jpet.103.060574

Cited by 59 publications

(48 citation statements)

References 30 publications

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“…Moreover, inhibition of PLC␤3 by local injection of U73122 into the hind paw has been shown to attenuate acute and chronic inflammatory hyperalgesia induced by unilateral carrageenan injection at the same site (9). These models clearly differ from the SNI used in the present study, which monitors neuropathic pain (12,13) and applies the inhibitor systemically.…”

Section: Discussionmentioning

confidence: 51%

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Phospholipase Cβ3 in mouse and human dorsal root ganglia and spinal cord is a possible target for treatment of neuropathic pain

Shi¹,

Liu²,

Hammarberg

et al. 2008

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

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Treatment of neuropathic pain is a major clinical problem. This study shows expression of phospholipase ß3 (PLCß3) in mouse and human DRG neurons, mainly in small ones and mostly with a nonpeptidergic phenotype. After spared nerve injury, the pain threshold was strongly reduced, and systemic treatment of such animals with the unselective PLC inhibitor U73122 caused a rapid and long-lasting (48-h) increase in pain threshold. Thus, inhibition of PLC may provide a way to treat neuropathic pain.galanin receptor 2 ͉ nerve injury ͉ neuropeptide ͉ pain treatment ͉ sensory neuron T he phospholipase C (PLC) family consists of several isoforms, such as PLC␤, ␥, ␦, and , which are linked to membrane receptors mediating intracellular signaling cascades (1-3). PLC has been demonstrated in dorsal root ganglion (DRG) neurons (4-6). Of the 4 major PLC␤ isoforms, PLC␤1, -␤3, and -␤4 expressed in DRGs, the PLC␤3 transcript shows the clearly highest levels (5).Involvement of PLC␤3 in regulation of pain and related sensations at the spinal level has been demonstrated in several studies. For example, PLC␤3 Ϫ/Ϫ mice show enhanced morphine responsiveness (7) and have a deficient scratching (''itching'') behavior (5). Bradykinin-and nerve growth factor-induced hypersensitivity involves PLC␤3 activation (8), and PLC␤3 is important for PKC 2 -mediated acute and chronic inflammatory pain (6). Other isoforms of PLC␤ have also been associated with pain. Thus, there is evidence that PLC␤1 is involved in the thermal nociceptive response (10), and PLC␤4 Ϫ/Ϫ mice show attenuated nociceptive behavior in the second phase of the formalin test, resulting from the tissue inflammation (11). Moreover, inhibition of PLC has been shown to attenuate acute and chronic inflammatory hyperalgesia (9).In the present study, we have monitored pain thresholds and the effect of an unselective PLC inhibitor (U73122) in the spared nerve injury (SNI) model of neuropathic pain in mouse (12, 13). In parallel we have analyzed the localization of PLCß3 and a number of transmitter related markers in DRGs and spinal cord and the effect of SNI. Human DRGs were also studied.Results SNI-Induced Hyperalgesia. After SNI, mice developed mechanical allodynia-like behavior as shown by the decrease in withdrawal threshold of the hindpaw ipsilateral to the nerve injury. This was seen 2 days after the surgery, with a pronounced effect between 7 and 21 days (Fig. 1A). A decrease, albeit less pronounced, was also seen in the contralateral hindpaw between day 7 and 21 after nerve injury (Fig. 1A).

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Section: Discussionmentioning

confidence: 51%

“…Thus, there is evidence that PLC␤1 is involved in the thermal nociceptive response (10), and PLC␤4 Ϫ/Ϫ mice show attenuated nociceptive behavior in the second phase of the formalin test, resulting from the tissue inflammation (11). Moreover, inhibition of PLC has been shown to attenuate acute and chronic inflammatory hyperalgesia (9).…”

mentioning

confidence: 99%

Phospholipase Cβ3 in mouse and human dorsal root ganglia and spinal cord is a possible target for treatment of neuropathic pain

Shi¹,

Liu²,

Hammarberg

et al. 2008

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

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“…PLC-β2 and PLC-β3 were shown to be crucial for neutrophil activation induced by chemokines (40). Our results indicate that GRP activates the PLC-β2 isoform, because the U-73122 inhibitor is specific for this isoenzyme (41). We propose that GRP is a ligand of the alternative signaling pathway.…”

Section: Discussionmentioning

confidence: 66%

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Czepielewski

Porto

Rizzo

et al. 2011

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

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Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.

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“…Carrageenin, a waterextractable polysaccharide obtained from various seaweeds, induces macrophage accumulation in fluid exudates from subcutaneous chambers in dogs (Hou et al 2004). Carrageenin activates kinin release and induces kinin B1 receptor (Campos et al 1996;Decarie et al 1996;Ni et al 2003).…”

Section: Discussionmentioning

confidence: 99%