A bright future? Optogenetics in the periphery for pain research and therapy

Mickle, Aaron D.; Gereau, Robert W.

doi:10.1097/j.pain.0000000000001329

Cited by 25 publications

(17 citation statements)

References 120 publications

(213 reference statements)

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“…However, the behavioral paradigm can easily be expanded to address other aspects of nociception by leveraging various genetic techniques. For example, inducible Cre-driver lines could provide developmental specificity in ChR2 expression 44 , while the implementation of other transgenic lines such as the SNS-ChR2 45 and MrgD-ChR2 28 could be used to investigate additional sub-populations of afferents that mediate other pain modalities. Such studies would be natural future extensions of the current work.…”

Section: Discussionmentioning

confidence: 99%

Automated and rapid self-report of nociception in transgenic mice

Black

Allawala

Bloye

et al. 2020

Sci Rep

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there are currently no rapid, operant pain behaviors in rodents that use a self-report to directly engage higher-order brain circuitry. We have developed a pain detection assay consisting of a lick behavior in response to optogenetic activation of predominantly nociceptive peripheral afferent nerve fibers in head-restrained transgenic mice expressing ChR2 in TRPV1 containing neurons. TRPV1-ChR2-EYFP mice (n = 5) were trained to provide lick reports to the detection of light-evoked nociceptive stimulation to the hind paw. Using simultaneous video recording, we demonstrate that the learned lick behavior may prove more pertinent in investigating brain driven pain processes than the reflex behavior. Within sessions, the response bias of transgenic mice changed with respect to lick behavior but not reflex behavior. Furthermore, response similarity between the lick and reflex behaviors diverged near perceptual threshold. our nociceptive lick-report detection assay will enable a host of investigations into the millisecond, single cell, neural dynamics underlying pain processing in the central nervous system of awake behaving animals. The importance of the brain in nociception has been theorized since Descartes' Treatise of Man 1. Melzack and Wall, whose gate control theory highlights the role of the spinal cord in pain processing, acknowledged the need for the myriad, interconnected brain areas to synthesize the perception of pain 2. Advances in human neural recording technologies have allowed scientists to test theories describing how brain circuits map onto pain 3. Human functional MRI (fMRI) has shown that perceived pain correlates with activation of primary somatosensory cortices, anterior cingulate cortex, and other brain regions implicated in the discriminatory and affective components of pain 4,5. Electroencephalography (EEG) and magnetoencephalography (MEG) have implicated the regulation of specific oscillatory components, for example alpha oscillations in the sensorimotor cortex, in pain perception 6. While techniques such as fMRI, EEG, and MEG paint a macroscopic picture of brain dynamics, these techniques cannot achieve the cellular or temporal resolution necessary for elucidating the neural circuits underlying pain perception. Genetic manipulations 7 and in vivo neural recordings in rodents are foundational in this respect as they afford the granularity required to characterize neural circuit activity and therapeutic outcomes 8-10. Unfortunately, the inability to compare behavioral outputs between animal and human studies presents a significant barrier for clinical translation of experimental results. Pain in humans is primarily measured using verbal self-reports, such as the visual analogue scale 11 , while pain in rodents is inferred from behavioral signals of discomfort, such as reflex behaviors 11,12. Reflex behaviors, like the hind paw withdrawal, are used to characterize evoked pain. Although reflex behaviors have been shown to positively correlate with self-reports of pain in humans 13 , decerebrated ...

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Section: Discussionmentioning

confidence: 99%

Automated and rapid self-report of nociception in transgenic mice

Black

Allawala

Bloye

et al. 2020

Sci Rep

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“…While in vivo cross-species comparisons have previously been made [47], in vitro transcriptome comparisons between mice and human DRGs have not been performed, despite the obvious need for such knowledge given the reliance on the mouse model for both target and drug discovery work in the pain area [14; 35; 46; 59; 70]. Certain perturbation studies [43] like gene expression knockdowns, DNA editing or optogenetic optimization [36], especially in the context of human research, cannot be performed in vivo , causing DRG cultures to be essential to human clinical translational research. Our work, therefore, gives fundamental new insight into some of the most commonly used model systems in the pain field with important implications for future work.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets

Wangzhou

McIlvried²,

Paige

et al. 2019

Preprint

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words)Dorsal root ganglion (DRG) neurons detect sensory inputs and are crucial for pain processing.They are often studied in vitro as dissociated cell cultures with the assumption that this reasonably represents in vivo conditions. However, to our knowledge, no study has ever directly compared genome-wide transcriptomes of DRG tissue in vivo versus in vitro, or between different labs and culturing protocols. We extracted bilateral lumbar DRG from C57BL6/J mice and human organ donors, and acutely froze one side and processed the other side as a dissociated cell culture, which was then maintained in vitro for 4 days. RNA was extracted and sequenced using the NextSeq Illumina platform. Comparing native to cultured human or mouse DRG, we found that the overall expression level of many ion channels and GPCRs specifically expressed in neurons is markedly lower in culture, but still expressed. This suggests that most pharmacological targets expressed in vivo are present in culture conditions. However, there are changes in expression levels for these genes. The reduced relative expression for neuronal genes in human DRG cultures is likely accounted for by increased expression of genes in fibroblast-like and other proliferating cells, consistent with the mitotic status of many cells in these cultures. We did find a subset of genes that are typically neuronally expressed, increased in human and mouse DRG cultures, including genes associated with nerve injury and/or inflammation in preclinical models such as BDNF, MMP9, GAL, and ATF3. We also found a striking upregulation of a number of inflammation-associated genes in DRG cultures, although many were different between mouse and human. Our findings suggest an injury-like phenotype in DRG cultures that has important implications for the use of this model system for pain drug discovery. Methods Experimental DesignBecause genetic variation can be a possible contributor to transcriptome level differences in nervous system samples from human populations [39; 41], we chose a study design wherein we cultured lumbar DRGs from one side in human donors and immediately froze the opposite side from the same donor for RNA sequencing. Although we used an inbred mouse strain (C57BL/6) for parallel mouse studies, we used a similar culturing design where cultures were done in two independent laboratories to look for variability across labs. RNA sequencing was performed at 4 days in vitro (DIV) to stay within the electrophysiologically relevant range of 1 -7 DIV for human DRG and the biochemical assay range of 4 -7 DIV for both human and mouse DRG. AnimalsPrice Lab: All procedures were approved by the Institutional Animal Care and Use Committee of University of Texas at Dallas and were in strict accordance with the US National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals. Adult C57Bl/6 mice (8-15 weeks of age) were bred in house, and were originally obtained from The Jackson Laboratory. Animals were housed in the University of Texas at Dallas animal facilities o...

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“…Study of the influence of genetic backgrounds that favor pain chronicity will also be needed, as will increased use of human neurons derived from stem cells for disease modeling and phenotypic screening, with enhanced focus on targeting activity in selective cell types (8,(77)(78)(79)(80). In addition, an adoption of more sophisticated means to study the nervous system, including optogenetics to selectively activate or suppress defined neuronal populations (81)(82)(83) and the imaging of large neuronal populations in awake unrestrained animals as a readout of nociceptive circuit activity (84), will be vital. It is critical that we also adapt the use of high spatial and temporal measures of behavior, with analysis based on machine learning and artificial intelligence to detect pain-related behaviors in an unbiased, observer-free, and automated way (85).…”

Section: How Can We Most Effectively Find Novel Targets?mentioning

confidence: 99%

Capturing Novel Non-opioid Pain Targets

Woolf

2020

Biological Psychiatry

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The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a major driver of the opioid crisis, together with the availability, overprescription, and diversion of these drugs. Eliminating opioids without an effective replacement is, however, no solution, as it substitutes one major problem with another. To deal successfully with the opioid crisis, we need to discover novel analgesics whose mechanisms do not involve the mu opioid receptor but that have high analgesic potency and low risk of adverse effects, particularly no abuse liability. The question is how to achieve this. There are several necessary elements; first, we need to understand the nature of pain and the mechanisms responsible for it, and second, we need to adopt novel and unbiased approaches to the identification and validation of pain targets.

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A bright future? Optogenetics in the periphery for pain research and therapy

Cited by 25 publications

References 120 publications

Automated and rapid self-report of nociception in transgenic mice

Automated and rapid self-report of nociception in transgenic mice

Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets

Capturing Novel Non-opioid Pain Targets

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