Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms

Eskander, Michael; Ruparel, Shivani; Green, Dustin P.; Chen, Paul B.; Por, Elaine D.; Jeske, Nathaniel Aaron; Gao, Xiaoli; Flores, Eric R.; Hargreaves, Kenneth M.

doi:10.1523/jneurosci.3993-14.2015

Cited by 94 publications

(91 citation statements)

References 55 publications

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“…Moreover, concentrations of lipids from the LOX and COX-2 pathway, which have previously been identified as modulators of TRP channels in various pain models (31-33), were not increased during PIPN. Previous reports suggest a role for CYP and LOX metabolites in NGFdependent thermal and mechanical nociception, and inhibition of CYP and LOX enzymes with the unspecific inhibitor NDGA may reduce NGF-dependent hypersensitivity (34). However, in our study, the concentrations of LOX products, such as HETEs, were either not changed or even decreased in DRGs and the spinal cord during PIPN.…”

Section: Discussioncontrasting

confidence: 84%

Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain

Sisignano

Angioni

Park

et al. 2016

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

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Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose-and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P 450 -epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxeltreated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxeltreated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.chemotherapy-induced neuropathy | neuropathic pain | TRPV1 | telmisartan | oxidized lipids R ecent studies identified members of the transient receptor potential-family of ion channels (TRPV1, TRPA1, and TRPV4) as contributors to both mechanical and cold allodynia during oxaliplatin and paclitaxel-induced neuropathy (1-5). Activation or sensitization of TRPV1 and TRPA1 can lead to enhanced release of CGRP and substance P, both of which can cause neurogenic inflammation and recruitment of T cells (6, 7).However, it remains unclear which endogenous mediators are involved in paclitaxel-dependent activation or sensitization of TRP channels, as paclitaxel cannot directly activate TRP channels (4,5,8). Interestingly, paclitaxel is an inducer of some Cytochrome-P 450 epoxygenases (e.g., CYP2C8, CYP2C9) (9). CYP epoxygenases can metabolize ω-6 fatty acids, such as arachidonic acid (AA) and linoleic acid (LA), generating either lipid epoxides such as EETs (epoxyeicosatrienoid acids) or ω-hydroxides such as 20-hydroxyeicosatetraenoic acid (20-HETE) (10, 11).Although therapeutic alternatives exist, paclitaxel is still the preferred first line of therapy for metastatic breast cancer (12), causing severe CIPNP in many treated patients. Here, we performed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipid profiling of sciatic nerve, dorsal root ganglion (DRG), and dorsal horn tissue from paclitaxel-treated mice.We identified 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid), a CYP metabolite of LA, to be strongly synthesized in DRGs 24 h and 8 d after paclitaxel injection in mice. 9,10-EpOME is capable of sensitizing TRPV1 at submicromolar concentrations via a cAMP-PKA-dependent mechanism, causing enhanced frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons of the spin...

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Section: Discussioncontrasting

confidence: 84%

Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain

Sisignano

Angioni

Park

et al. 2016

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

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“…The capsaicin receptor TRPV1 is expressed in C-fiber nociceptive neurons and upregulated in DRG neurons after inflammation and nerve injury (Ji et al, 2002; Obata et al, 2004). TRPV1 regulates heat transduction and is especially critical for the development of heat hyperalgesia (Caterina et al, 2000; Davis et al, 2000; Eskander et al, 2015). We tested capsaicin-induced pain in WT and Shank3 mutant mice.…”

Section: Resultsmentioning

confidence: 99%

“…As a functional measurement of presynaptic modulation, TRPV1-medicated mEPSC frequency increase in spinal lamina IIo neurons is substantially reduced in Shank3 mutant mice. Spinal TRPV1 was also implicated in the generation of mechanical allodynia (Eskander et al, 2015; Kim et al, 2012). Consistently, mechanical allodynia after CFA and CCI was partially reduced in Shank3 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons

Han

Kim

Wang

et al. 2016

Neuron

127

129

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SUMMARY Abnormal pain sensitivity is commonly associated with autism spectrum disorders (ASDs) and affects the life quality of ASD individual. SHANK3 deficiency was implicated in ASD and pain dysregulation. Here we report functional expression of SHANK3 in mouse dorsal root ganglion (DRG) sensory neurons and spinal cord presynaptic terminals. Homozygous and heterozygous Shank3 complete knockout (Δe4–22) results in impaired heat hyperalgesia in inflammatory and neuropathic pain. Specific deletion of Shank3 in Nav1.8-expressing sensory neurons also impairs heat hyperalgesia in homozygous and heterozygous mice. SHANK3 interacts with transient receptor potential subtype V1 (TRPV1) via Proline-rich region and regulates TRPV1 surface expression. Furthermore, capsaicin-induced spontaneous pain, inward currents in DRG neurons, and synaptic currents in spinal cord neurons are all reduced after Shank3 haploinsufficiency. Finally, partial knockdown of SHANK3 expression in human DRG neurons abrogates TRPV1 function. Our findings reveal a peripheral mechanism of SHANK3, which may underlie pain deficits in SHANK3-related ASDs.

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“…However, a large number of studies utilizing multiple animal models of inflammatory pain-like conditions have since suggested a critical role for TRPV1 in inflammatory mechanical hypersensitivity. These studies show attenuation of mechanical hypersensitivity by: (a) specific small molecule antagonists of TRPV1; and/or (b) administration of inflammatory mediators (or induction of inflammatory/disease conditions) in Trpv1 −/− mice [85,128,129,130,131,132,133,134]. In addition to TRPV1, TRPA1 has also been proposed to be involved in inflammatory mechanical hyperalgesia.…”

Section: Involvement Of Nociceptive Trp Channels In Painful Patholmentioning

confidence: 99%

Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

2016

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Specialized receptors belonging to the transient receptor potential (TRP) family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics.

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Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms

Cited by 94 publications

References 55 publications

Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain

Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain

SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons

Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

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