Translational profiling of dorsal root ganglia and spinal cord in a mouse model of neuropathic pain

Uttam, Sonali; Wong, Calvin; Amorim, Inês S.; Jafarnejad, Seyed Mehdi; Tansley, Shannon; Yang, Jieyi; Prager‐Khoutorsky, Masha; Mogil, Jeffrey S.; Gkogkas, Christos G.; Khoutorsky, Arkady

doi:10.1016/j.ynpai.2018.04.001

Cited by 53 publications

(35 citation statements)

References 52 publications

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“…However, excitatory DYN + neurons are largely restricted to mid-lumbar DH (corresponding to glabrous skin territory) (Huang et al 2018), and transcriptomic clusters do not seem to reflect these differences. Finally, it will be critical to determine whether these molecular markers remain unchanged after injury, as mRNA expression undergoes important regulations in persistent pain states (Tansley et al 2018;Uttam et al 2018).…”

Section: Classification Of Dorsal Horn Neuron Populations: Pitfalls Amentioning

confidence: 99%

Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia

2020

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The dorsal horns of the spinal cord and the trigeminal nuclei in the brainstem contain neuron populations that are critical to process sensory information. Neurons in these areas are highly heterogeneous in their morphology, molecular phenotype and intrinsic properties, making it difficult to identify functionally distinct cell populations, and to determine how these are engaged in pathophysiological conditions. There is a growing consensus concerning the classification of neuron populations, based on transcriptomic and transductomic analyses of the dorsal horn. These approaches have led to the discovery of several molecularly defined cell types that have been implicated in cutaneous mechanical allodynia, a highly prevalent and difficult-to-treat symptom of chronic pain, in which touch becomes painful. The main objective of this review is to provide a contemporary view of dorsal horn neuronal populations, and describe recent advances in our understanding of on how they participate in cutaneous mechanical allodynia.

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Section: Classification Of Dorsal Horn Neuron Populations: Pitfalls Amentioning

confidence: 99%

Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia

2020

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“…The first, ribosome footprint profiling, comprehensively and quantitatively provides a snapshot of translation activity at single codon resolution through deep sequencing of ribosome-protected mRNA fragments from cells or tissues (Ingolia, 2016). This technique, which has recently been applied to the DRG (Uttam et al, 2018), does not allow insight into cell-type-specific translational profiling. A second technique is translating ribosome affinity purification (TRAP), which relies on genetic tagging of ribosomal proteins for cell-specific pulldown of translating ribosomes bound to mRNAs for RNA-seq (Doyle et al, 2008;Heiman et al, 2008Heiman et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling

Megat¹,

Ray²,

Tavares‐Ferreira³

et al. 2019

J. Neurosci.

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Nociceptors located in the trigeminal ganglion (TG) and DRG are the primary sensors of damaging or potentially damaging stimuli for the head and body, respectively, and are key drivers of chronic pain states. While nociceptors in these two tissues show a high degree of functional similarity, there are important differences in their development lineages, their functional connections to the CNS, and recent genome-wide analyses of gene expression suggest that they possess some unique genomic signatures. Here, we used translating ribosome affinity purification to comprehensively characterize and compare mRNA translation in Scn10a-positive nociceptors in the TG and DRG of male and female mice. This unbiased method independently confirms several findings of differences between TG and DRG nociceptors described in the literature but also suggests preferential utilization of key signaling pathways. Most prominently, we provide evidence that translational efficiency in mechanistic target of rapamycin (mTOR)-related genes is higher in the TG compared with DRG, whereas several genes associated with the negative regulator of mTOR, AMP-activated protein kinase, have higher translational efficiency in DRG nociceptors. Using capsaicin as a sensitizing stimulus, we show that behavioral responses are greater in the TG region and this effect is completely reversible with mTOR inhibition. These findings have implications for the relative capacity of these nociceptors to be sensitized upon injury. Together, our data provide a comprehensive, comparative view of transcriptome and translatome activity in TG and DRG nociceptors that enhances our understanding of nociceptor biology.

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“…9,10 GIRK channel subunits have been detected in dorsal root ganglion (DRG) neurons of rats and humans, [11][12][13][14] and mice. 15,16 Opiates are known to be highly effective in acute pain and acute inflammatory pain, [17][18][19][20][21] but are less effective in neuropathic pain patients or animal models. After peripheral nerve injury, the GIRK1 and −2 proteins are significantly downregulated in DRGs and spinal dorsal horn.…”

Section: Introductionmentioning

confidence: 99%

<p>G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 is Upregulated in Rat DRGs and Spinal Cord After Peripheral Nerve Injury</p>

Lyu

Mulder

et al. 2020

JPR

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Background: G protein-gated inwardly rectifying potassium (GIRK) channels are involved in the regulation of neuronal excitability. Four GIRK subunits (GIRK1-4) are expressed in rat dorsal root ganglia (DRGs). Recently, we have characterized the expression of GIRK1 and −2, and both are downregulated in rat DRGs and spinal cord after a complete sciatic nerve transection (axotomy). Here, we aimed to study the neurochemical characteristics of GIRK3, and its regulation in rat DRGs and spinal cord induced by nerve injury. Methods: A sciatic nerve axotomy was performed to study the influences of injury on GIRK3 expression in DRGs and spinal cord. A dorsal root rhizotomy and a sciatic nerve crush were employed to study the axonal transport of GIRK3 protein, respectively. Immunohistochemistry analysis was employed for investigating the neurochemical characteristics of GIRK3. Results: In control DRGs,~18% of neuron profiles (NPs) were GIRK3-positive (+), and 41%,~48% and~45% of GIRK3 + NPs were CGRP + , IB4 + and NF200 + , respectively. GIRK3-like immunoreactivity was observed in glabrous skin of hind paws and axons originating from DRG neurons. Fourteen days after axotomy, more than one-third of DRG NPs were GIRK3 + , and among these~51% and~56% coexpressed galanin and neuropeptide Y, respectively. In control animals, a small group of interneurons found in the dorsal horn was GIRK3 +. In addition, GIRK3 + processes could be observed in superficial laminae of spinal dorsal horn. After nerve injury, the intensity of GIRK3-like immunoreactivity in the superficial layers was increased. Evidence based on rhizotomy and sciatic nerve crush indicated both anterograde and retrograde transport of GIRK3. Conclusion: Our study demonstrates that GIRK3 is expressed in sensory neurons and spinal cord. GIRK3 has both anterograde and retrograde axonal transport. GIRK3 expression can be regulated by peripheral nerve injury.

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Translational profiling of dorsal root ganglia and spinal cord in a mouse model of neuropathic pain

Cited by 53 publications

References 52 publications

Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia

Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia

Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling

<p>G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 is Upregulated in Rat DRGs and Spinal Cord After Peripheral Nerve Injury</p>

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