Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source

Weir, Greg A.; Middleton, Steven J; Clark, Alex; Daniel, Tarun; Khovanov, Nikita; McMahon, Stephen B.; Bennett, David L.H.

doi:10.1093/brain/awx201

Cited by 56 publications

(70 citation statements)

References 72 publications

(116 reference statements)

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“… 11 , 14 , 17 , 32 In fact, this transcription factor is currently considered as a nerve injury marker. 14 , 33 Actually, it has been speculated that ATF3 could contribute to formalin-induced long-lasting behavioral effects. 11 As expected, we found that nerve injury up-regulated ATF3 expression mainly in L5 and L6 DRGs and spinal cord.…”

Section: Discussionmentioning

confidence: 99%

ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

et al. 2018

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Transcription factors are proteins that modulate the transcriptional rate of target genes in the nucleus in response to extracellular or cytoplasmic signals. Activating transcription factors 2 (ATF2) and 3 (ATF3) respond to environmental signals and maintain cellular homeostasis. There is evidence that inflammation and nerve injury modulate ATF2 and ATF3 expression. However, the function of these transcription factors in pain is unknown. The purpose of this study was to investigate the contribution of ATF2 and ATF3 to nerve injury-induced neuropathic pain. L5/6 spinal nerve ligation induced tactile allodynia and thermal hyperalgesia. Moreover, nerve damage enhanced ATF2 and ATF3 protein expression in injured L5/6 dorsal root ganglia and spinal cord but not in uninjured L4 dorsal root ganglia. Nerve damage also enhanced ATF2 immunoreactivity in dorsal root ganglia and spinal cord 7 to 21 days post-injury. Repeated intrathecal post-treatment with a small-interfering RNA targeted against ATF2 (ATF2 siRNA) or anti-ATF2 antibody partially reversed tactile allodynia and thermal hyperalgesia. In contrast, ATF3 siRNA or anti-ATF3 antibody did not modify nociceptive behaviors. ATF2 immunoreactivity was found in dorsal root ganglia and spinal cord co-labeling with NeuN mainly in non-peptidergic (IB4+) but also in peptidergic (CGRP+) neurons. ATF2 was found mainly in small- and medium-sized neurons. These results suggest that ATF2, but not ATF3, is found in strategic sites related to spinal nociceptive processing and participates in the maintenance of neuropathic pain in rats.

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Section: Discussionmentioning

confidence: 99%

ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

et al. 2018

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“…Therefore, results from DREADD studies hold great potential, but should be interpreted with caution and their future clinical use through gene therapy must control for certain risks. An alternative, but similar approach has recently been developed whereby viral transduction of an engineered chloride-channel sensitive to ivermectin (GluCl v2.0) was capable of long-term repeatable suppression of sensory neuron sensitivity and amelioration of neuropathic pain in rodents; the expression of GluCl v2.0 in human-induced pluripotent stem cell derived sensory neurones was also shown to cause their silencing in an ivermectin-dependent manner [ 38 ]. Overall, the ability to selectively control the excitability of neuronal subpopulations using either chemo- or optogenetic tools offers an attractive way of treating neuropathic pain compared to orally taken medications, which result in the whole body being exposed to the drug.…”

Section: Nociceptors: Transducers Of Painmentioning

confidence: 99%

Advances in understanding nociception and neuropathic pain

Smith

2017

J Neurol

184

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Pain results from the activation of a subset of sensory neurones termed nociceptors and has evolved as a “detect and protect” mechanism. However, lesion or disease in the sensory system can result in neuropathic pain, which serves no protective function. Understanding how the sensory nervous system works and what changes occur in neuropathic pain are vital in identifying new therapeutic targets and developing novel analgesics. In recent years, technologies such as optogenetics and RNA-sequencing have been developed, which alongside the more traditional use of animal neuropathic pain models and insights from genetic variations in humans have enabled significant advances to be made in the mechanistic understanding of neuropathic pain.

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“…Early methods involved the gene transfer using GAD65 using herpes simplex viral vectors to enhance inhibitory tone (Liu et al, 2004). More recent efforts have used the delivery of adeno-associated virus (AAV) containing glutamate activated chloride channels to peripheral neurons to promote long lasting pain relief by increasing hyperpolarizing GABA currents after ivermectin (designer drug) administration (Weir et al, 2017). Not all of these strategies will necessarily target neurons, delivery of anti-inflammatory cytokine IL-10 using lentiviral mediated transfer has also shown promise for neuropathic pain (He et al, 2013).…”

Section: Genetic Therapiesmentioning

confidence: 99%

Developing Modern Pain Therapies

et al. 2019

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Chronic pain afflicts as much as 50% of the population at any given time but our methods to address pain remain limited, ineffective and addictive. In order to develop new therapies an understanding of the mechanisms of painful sensitization is essential. We discuss here recent progress in the understanding of mechanisms underlying pain, and how these mechanisms are being targeted to produce modern, specific therapies for pain. Finally, we make recommendations for the next generation of targeted, effective, and safe pain therapies.

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Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source

Cited by 56 publications

References 72 publications

ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

Advances in understanding nociception and neuropathic pain

Developing Modern Pain Therapies

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