A Synthetic Cell-Penetrating Peptide Antagonizing TrkA Function Suppresses Neuropathic Pain in Mice

Ma, Wei-Ying; Murata, Eri; Ueda, Koyo; Kuroda, Yoshihiro; Cao, Minghui; Abe, Mineo; Shigemi, Kenji; Hirose, Munetaka

doi:10.1254/jphs.10119fp

Cited by 17 publications

(13 citation statements)

References 25 publications

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“…Gene expression of Ccl12 was significantly reduced at both 14 and 28 days post-exposure whereas only Il1β gene expression was significantly depressed at 28 days post-exposure. Ntrk1 , Kcnq3 and Oprd1 play important roles in neuropathic pain (Benbouzid et al, 2008; Dondio et al, 2001; Dost et al, 2004; Fritch et al, 2010; Ma et al, 2010; Shinoda et al, 2007; Ugolini et al, 2007) while Ccl12 , Tlr2 , and Il1β are involved in inflammation (Gundra et al, 2011; Mojsilovic-Petrovic et al, 2007; Niven et al, 2015; Oh et al, 2012; Yang et al, 2009). Ntrk1 also may be a part of a negative feedback loop linking neuropathic pain and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Manohar

Dahar

Adler

et al. 2016

Molecular and Cellular Neuroscience

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Severe noise-induced damage to the inner ear leads to auditory nerve fiber degeneration thereby reducing the neural input to the cochlear nucleus (CN). Paradoxically, this leads to a significant increase in spontaneous activity in the CN which has been linked to tinnitus, hyperacusis and ear pain. The biological mechanisms that lead to an increased spontaneous activity are largely unknown, but could arise from changes in glutamatergic or GABAergic neurotransmission or neuroinflammation. To test this hypothesis, we unilaterally exposed rats for 2 h to a 126 dB SPL narrow band noise centered at 12 kHz. Hearing loss measured by auditory brainstem responses exceeded 55 dB from 6 to 32 kHz. The mRNA from the exposed CN was harvested at 14 or 28 days post-exposure and qRT-PCR analysis was performed on 168 genes involved in neural inflammation, neuropathic pain and glutamatergic or GABAergic neurotransmission. Expression levels of mRNA of Slc17a6 and Gabrg3, involved in excitation and inhibition respectively, were significantly increased at 28 days post-exposure, suggesting a possible role in the CN spontaneous hyperactivity associated with tinnitus and hyperacusis. In the pain and inflammatory array, noise exposure up-regulated mRNA expression levels of four pain/inflammatory genes, Tlr2, Oprd1, Kcnq3 and Ntrk1 and decreased mRNA expression levels of two more genes, Ccl12 and Il1β. Pain/inflammatory gene expression changes via Ntrk1 signaling may induce sterile inflammation, neuropathic pain, microglial activation and migration of nerve fibers from the trigeminal nerve and cuneate and vestibular nuclei into the CN. These changes could contribute to somatic tinnitus, hyperacusis and otalgia.

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Section: Discussionmentioning

confidence: 99%

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Manohar

Dahar

Adler

et al. 2016

Molecular and Cellular Neuroscience

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“… Anti-NGF blocking antibodies  TrkAd5 Watson et al, 2008;McNamee et al, 2010  Anti-TrkA blocking antibodies  TrkA antagonists Watson et al, 2008  Kinase inhibitors  Inhibitory peptides Martin et al, 2011;Ueda et al, 2010;Ma et al, 2010 Fig (1996). Basophil priming by neurotrophic factors.…”

Section: Trka Ngfmentioning

confidence: 99%

Expression and Role of the TrkA Receptor in Pulmonary Inflammatory Diseases

Freund-Michel¹,

Müller²,

Frossard³

2011

Inflammatory Diseases - A Modern Perspective

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“…Such changes in anatomical and physiological properties of nociceptors may contribute to development of conditions such as autonomic dysreflexia (e.g., Marsh et al, 2002). TrkA antagonists prevent the sensitization (thermal and mechanical hyperalgesia) normally induced by partial nerve injury (Ma et al, 2010), and antagonism of TrkA signaling has been effective for controlling human pain (Mantyh et al, 2011). Hence, elevation in the levels of TrkA and NGF in response to contusive injury could play a role in some of the maladaptive processes after incomplete SCI.…”

Section: Discussionmentioning

confidence: 99%

The Transcriptional Response of Neurotrophins and Their Tyrosine Kinase Receptors in Lumbar Sensorimotor Circuits to Spinal Cord Contusion is Affected by Injury Severity and Survival Time

Hougland¹,

Harrison²,

Magnuson³

et al. 2013

Front. Physio.

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Traumatic spinal cord injury (SCI) results in changes to the anatomical, neurochemical, and physiological properties of cells in the central and peripheral nervous system. Neurotrophins, acting by binding to their cognate Trk receptors on target cell membranes, contribute to modulation of anatomical, neurochemical, and physiological properties of neurons in sensorimotor circuits in both the intact and injured spinal cord. Neurotrophin signaling is associated with many post-SCI changes including maladaptive plasticity leading to pain and autonomic dysreflexia, but also therapeutic approaches such as training-induced locomotor improvement. Here we characterize expression of mRNA for neurotrophins and Trk receptors in lumbar dorsal root ganglia (DRG) and spinal cord after two different severities of mid-thoracic injury and at 6 and 12 weeks post-SCI. There was complex regulation that differed with tissue, injury severity, and survival time, including reversals of regulation between 6 and 12 weeks, and the data suggest that natural regulation of neurotrophins in the spinal cord may continue for months after birth. Our assessments determined that a coordination of gene expression emerged at the 12-week post-SCI time point and bioinformatic analyses address possible mechanisms. These data can inform studies meant to determine the role of the neurotrophin signaling system in post-SCI function and plasticity, and studies using this signaling system as a therapeutic approach.

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A Synthetic Cell-Penetrating Peptide Antagonizing TrkA Function Suppresses Neuropathic Pain in Mice

Cited by 17 publications

References 25 publications

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Expression and Role of the TrkA Receptor in Pulmonary Inflammatory Diseases

The Transcriptional Response of Neurotrophins and Their Tyrosine Kinase Receptors in Lumbar Sensorimotor Circuits to Spinal Cord Contusion is Affected by Injury Severity and Survival Time

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