Persistent Pain after Spinal Cord Injury Is Maintained by Primary Afferent Activity

Yang, Qing; Wu, Zhao; Hadden, Julia K.; Odem, Max A.; Zuo, Yan; Crook, Robyn J.; Frost, Jeffrey A.; Walters, Edgar T.

doi:10.1523/jneurosci.5316-13.2014

Cited by 124 publications

(149 citation statements)

References 38 publications

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“…Injury is thought to activate intrinsic neuronal growth programs, including neurotrophin signaling, to promote axon regrowth (59). Neurotrophin release in response to injury also leads to inflammatory signaling, hyperalgesia, and aberrant sprouting in peripheral sensory neurons, resulting in potentially debilitating neuropathic pain (60)(61)(62)(63)(64)(65)(66)(67). Increased expression of TRPV2 was thought to contribute directly to pain sensation after nerve injury (58).…”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons

Cohen

Johnson

Pilat

et al. 2015

Molecular and Cellular Biology

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Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca 2؉ -permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca 2؉ -permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca 2؉ signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca 2؉ signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.E stablishment of precise neural connections during nervous system development is essential in forming functional circuits. Neurite outgrowth allows for connection and communication between developing neurons and their targets. In the developing peripheral nervous system, nerve growth factor (NGF) is a targetderived extracellular cue necessary for outgrowth (1). Upon binding to its extracellular receptor, NGF activates the phosphoinositide 3-kinase (PI3K) signaling pathway, which is essential for the survival of developing neurons, and the mitogen-activated protein kinase (MAPK) pathway, which promotes differentiation and neurite outgrowth (2, 3). These signaling pathways have numerous downstream effectors in developing neurons, including several Ca 2ϩ -permeable transient receptor potential (TRP) channels (4-8).Thermosensitive TRP channels from the vanilloid subfamily (thermoTRPV channels) consist of four nonselective Ca 2ϩ -permeable cation channels, TRP vanilloid 1 (TRPV1) to TRPV4, originally described as pain and temperature sensors in adult sensory neurons (9-12). Recent evidence suggests, however, that only TRPV1 functions as a molecular sensor of heat and painful stimuli in vivo, while the function of TRPV2 to -4 remains unclear (13-16). TRPV2 and TRPV4 have also been detected in developing peripheral neurons, suggesting that they may play a role in growth programs during development (17, 18). Consistent with this notion, TRPV2 has been implicated in axon outgrowth (18), and critical mutations in TRPV4 result in peripheral axonal neuropathies (19,20). Despite these initial findings, the details by which thermoTRPV channels influence neuronal development remain unknown.Here we explore the molecular mechanisms by which thermoTRPV channels contribute to neurotrophin-mediated peripher...

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Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons

Cohen

Johnson

Pilat

et al. 2015

Molecular and Cellular Biology

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“…In a previous study we suggested that the neural mechanisms that mediate apprehension are independent of those that mediate aversion measured with the PEAP test [2]. The analgesic effect of UR13870 should now be assessed with translational behavioral measures of non-evoked neuropathic pain [23,24] and also for evidence of reversal of established chronic pain behaviors.…”

Section: Discussionmentioning

confidence: 99%

Early treatment with UR13870, a novel inhibitor of p38α mitogenous activated protein kinase, prevents hyperreflexia and anxiety behaviors, in the spared nerve injury model of neuropathic pain

Galán-Arriero¹,

Ávila-Martín²,

Ferrer-Donato³

et al. 2015

Neuroscience Letters

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“…Spontaneous pain was tested using a conditioning paradigm with retigabine (#R-100, Alomone Laboratory, Jerusalem, Israel) as the conditioned stimulus to briefly relieve pain (45–60 minutes), as originally described in a rat model [6; 53]. Briefly, mice were first allowed to freely explore the conditioned place preference apparatus, which consists of 2 chambers (18 × 20 cm, 1 dark, 1 light) connected by a 15 cm hallway (Stoelting, Wood Dale, IL), for 15 minutes.…”

Section: Methodsmentioning

confidence: 99%

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy

Krukowski

Golonzhka

et al. 2017

Pain

148

152

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Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration–approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin–dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.

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Persistent Pain after Spinal Cord Injury Is Maintained by Primary Afferent Activity

Cited by 124 publications

References 38 publications

Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons

Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons

Early treatment with UR13870, a novel inhibitor of p38α mitogenous activated protein kinase, prevents hyperreflexia and anxiety behaviors, in the spared nerve injury model of neuropathic pain

HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy

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