The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

Janes, Kali; Little, Joshua W.; Li, Chao; Bryant, Leesa; Chen, Collin; Chen, Zhoumou; Kamocki, Krzysztof; Doyle, Tim; Snider, Ashley J.; Esposito, Emanuela; Cuzzocrea, Salvatore; Bieberich, Erhard; Obeid, Lina M.; Petrache, Irina; Nicol, Grant D.; Neumann, William L.; Salvemini, Daniela

doi:10.1074/jbc.m114.569574

Cited by 128 publications

(168 citation statements)

References 85 publications

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“…However, administration of a S1P1 agonist with a dose that evoked antinociceptive effects in chemically-induced neuropathy, was Brought to you by | EP Ipswich Authenticated Download Date | 5/5/15 8:17 AM not sufficient in trauma-induced neuropathy. These findings seem to contrast data published previously showing that activation of S1P1 is sufficient to reduce chemotherapy-induced neuropathic pain in the paclitaxel model through downregulation of S1P1 receptors in activated spinal microglia (Janes et al, 2014). However, the results presented here and in the previous report (Janes et al, 2014) highlight the differences between both models for neuropathic pain and show that FTY720 can decrease neuropathic pain using different mechanisms.…”

Section: Discussioncontrasting

confidence: 84%

“…S1P1 was expressed in high amounts in the dorsal horn of the murine spinal cord, a region with a high importance for spinal nociceptive processing, as well as at lower expression levels in central laminae, the ventral horn and throughout the white matter ( Figure 3A). The S1P1 expression throughout the white matter is in accordance with the reported S1P1 expression on spinal microglia (Janes et al, 2014). In contrast to S1P1, S1P3 expression was restricted to central areas and the ventral horn.…”

Section: Antinociceptive Effects Of Fty720 Are Mediated By Spinal S1psupporting

confidence: 88%

“…More recently, it was shown that activation of S1P1 receptors on microglia in the spinal cord induces the release of pro-inflammatory mediators (i.e. TNFα, IL1β) and decreases the release of the anti-inflammatory mediators IL10 during chemotherapy-induced neuropathies (Janes et al, 2014). Fittingly, downregulation of S1P1 on spinal microglia through FTY720 reduced the nociceptive behavior in one model of chemotherapy-induced neuropathic pain.…”

Section: Introductionmentioning

confidence: 98%

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Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

Zhang

Linke

Suo

et al. 2015

Biological Chemistry

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FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720. Accordingly, intrathecal administration of S1P1 receptor agonists was not sufficient to evoke an antinociceptive effect. Taken together, the data show that, in contrast to its effects on chemotherapy-induced neuropathy, FTY720 reduces trauma-induced neuropathic pain by simultaneous activation of spinal S1P1 and S1P3 receptor subtypes.

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Section: Discussioncontrasting

confidence: 84%

Section: Antinociceptive Effects Of Fty720 Are Mediated By Spinal S1psupporting

confidence: 88%

Section: Introductionmentioning

confidence: 98%

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Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

Zhang

Linke

Suo

et al. 2015

Biological Chemistry

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“…A 3 AR activation protects against the neurotoxic P2X7-mediated [62] or the glutamate and NMDA-mediated rise in Ca 2+ and thus neuronal excitability of neurons in vitro [61], suggesting that A 3 AR impacts glutamatergic signaling. While the underlying mechanisms of CIPN are multifactorial and include changes in the periphery [5], prominent neuropathological CNS changes have been implicated in the dysregulation of spinal neuro-glia communication brought about by neuroinflammatory processes [10,18,25]. For example, activation of NFκB and MAPKs (ERK, p38) [18,25] and overt production of pro-inflammatory cytokines (TNF-α, IL-1β) [10,18,25] have been reported.…”

Section: Introductionmentioning

confidence: 99%

A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways

Janes

Esposito

Doyle

et al. 2014

Pain

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Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol®). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite (PN) in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. PN in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (i.e., IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism(s) of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in a decreased production of neuroexcitatory/pro-inflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in CIPN patients.

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“…Multifunctional polymer-blend nanoparticle formulations were also used in drug-resistant breast cancer model (van Vlerken et al, 2008). Finally, it was shown that S1P receptor activation is required for the development and maintenance of paclitaxel-induced neuropathic pain (Janes et al, 2014). Additional work is necessary to analyze whether taxane-induced neuropathy can be circumvented by blocking the S1P/S1P receptor signaling without negatively influencing the effects of the drug on tumor cell death.…”

Section: Taxanesmentioning

confidence: 99%

Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways

Hajj

Becker-Flegler

Haimovitz‐Friedman

2015

Biological Chemistry

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Abstract:The prevailing mechanisms of action of traditional chemotherapeutic agents have been challenged by sphingolipid cancer research. Many studies have shown that ceramide generation in response to cytotoxic agents is central to tumor cell death. Ceramide can be generated either via hydrolysis of cell-membrane sphingomyelin by sphingomyelinases, hydrolysis of cerebrosides, or via de novo synthesis by ceramide synthases. Ceramide can act as a second messenger for apoptosis, senescence or autophagy. Inherent or acquired alterations in the sphingolipid pathway can account for resistance to the classic chemotherapeutic agents. In particular, it has been shown that activation of the acid ceramidase can lead to the formation of sphingosine 1-phosphate, which then antagonizes ceramide signaling by initiating a pro-survival signaling pathway. Furthermore, ceramide glycosylation catalyzed by glucosylceramide synthase converts ceramide to glucosylceramide, thus eliminating ceramide and consequently protecting cancer cells from apoptosis. In this review, we describe the effects of some of the most commonly used chemotherapeutic agents on ceramide generation, with a particular emphasis on strategies used to enhance the efficacy of these agents.

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The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

Cited by 128 publications

References 85 publications

Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways

Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways

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