The Persistent Pain Transcriptome: Identification of Cells and Molecules Activated by Hyperalgesia

Sapio, Matthew R.; Kim, Jaeyeon; Loydpierson, Amelia J.; Maric, Dragan; Goto, Taichi; Vazquez, Fernando A.; Dougherty, Mary Kate; Narasimhan, Radhika; Muhly, Wallis T.; Iadarola, Michael J.; Mannes, Andrew J.

doi:10.1016/j.jpain.2021.03.155

Cited by 7 publications

(6 citation statements)

References 157 publications

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“…We recently found that the majority of p-S10H3-expressing dynorphinergic neurons were Lmx1b-IR (83.3%) in laminae I-IIo following burn injury [ 6 ], suggesting that noxious thermal pain is probably processed by a distinct excitatory subgroup of Pdyn neurons in the SDH. In line with our observation, a recent comprehensive transcriptomics study revealed that the glutamatergic subset of Pdyn neurons mediates hyperalgesia induced by peripheral tissue damage in rats [ 40 ]. Interestingly, it has been reported that thermosensitive neurons in the lateral parabrachial nucleus (LPb), a relay nucleus for ascending somatosensory pathway for pain, produce dynorphin [ 41 ].…”

Section: Discussionsupporting

confidence: 88%

“…Combining novel biotechnological tools, we provided evidence for the importance of histone H3.1 phosphorylation at position S10 in the Pdyn neuron in the response to painful thermal stimulation. In certain pathological pain states (inflammation or nerve injury), this neuroepigenetic signal may be one of the molecular mechanisms that results in increased neuronal activity and consequential hyperalgesia through permissive transcription of certain pain-related genes such as prodynorphin itself [ 21 , 40 , 42 , 43 , 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

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CRISPR/Cas9-Based Mutagenesis of Histone H3.1 in Spinal Dynorphinergic Neurons Attenuates Thermal Sensitivity in Mice

Mészàr

Kókai

Varga

et al. 2022

IJMS

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Burn injury is a trauma resulting in tissue degradation and severe pain, which is processed first by neuronal circuits in the spinal dorsal horn. We have recently shown that in mice, excitatory dynorphinergic (Pdyn) neurons play a pivotal role in the response to burn-injury-associated tissue damage via histone H3.1 phosphorylation-dependent signaling. As Pdyn neurons were mostly associated with mechanical allodynia, their involvement in thermonociception had to be further elucidated. Using a custom-made AAV9_mutH3.1 virus combined with the CRISPR/cas9 system, here we provide evidence that blocking histone H3.1 phosphorylation at position serine 10 (S10) in spinal Pdyn neurons significantly increases the thermal nociceptive threshold in mice. In contrast, neither mechanosensation nor acute chemonociception was affected by the transgenic manipulation of histone H3.1. These results suggest that blocking rapid epigenetic tagging of S10H3 in spinal Pdyn neurons alters acute thermosensation and thus explains the involvement of Pdyn cells in the immediate response to burn-injury-associated tissue damage.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-Based Mutagenesis of Histone H3.1 in Spinal Dynorphinergic Neurons Attenuates Thermal Sensitivity in Mice

Mészàr

Kókai

Varga

et al. 2022

IJMS

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“…Ion channels and receptor genes were highlighted due to their relevance to pharmacology research. We selected receptor genes ≥ 1 sFPKM in any dataset, which is less stringent than the requirement of 5 sFPKM for the other datasets due to the fact that receptor genes are often lowly expressed in RNA-Seq studies ( Sapio et al, 2016 ; Sapio et al, 2018 ; Sapio et al, 2021 ). The interleukin 6 receptor ( Il6r ) was the most strongly regulated receptor gene and is one of the top 10 increasing genes overall with robust expression in all three brain regions (sFPKM ∼10–20).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, the highly expressed microglial marker genes C1qa and C1qb are also consistently induced, potentially due to microglial proliferation. The C1q complement signaling pathway has been previously identified in RNA-Seq studies in paradigms associated with microglial activation/proliferation ( Raithel et al, 2018 ; Sapio et al, 2021 ), and this signaling pathway has also been proposed as a mechanism for synaptic remodeling ( Stevens et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Activation, Deactivation and Rebound Patterns in Cortex, Hippocampus and Amygdala in Response to Ketamine Infusion in Rats

Kim

Sapio

Vazquez

et al. 2022

Front. Mol. Neurosci.

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Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, is a recently revitalized treatment for pain and depression, yet its actions at the molecular level remain incompletely defined. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways. A continuous intravenous administration paradigm for ketamine was developed in rat consisting of short (1 h) and long duration (10 h, and 10 h + 24 h recovery) infusions of anesthetic concentrations to activate or inhibit gene transcription in a pharmacokinetically controlled fashion. Transcription was measured by RNA-Seq in three brain regions: frontal cortex, hippocampus, and amygdala. Cellular level gene localization was performed with multiplex fluorescent in situ hybridization. Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9–12 significant genes per brain region, p < 0.01 per gene) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling (Nuclear Factor Erythroid-Derived 2-Like 2) containing 12–25 increasing genes (p < 0.01) per brain region. By 10 h of infusion, the acute results were further reinforced and consisted of more and stronger gene alterations reflecting a sustained and accentuated ketamine modulation of regional excitation and plasticity. At the cellular level, in situ hybridization localized up-regulation of the plasticity-associated gene Bdnf, and the transcription factors Nr4a1 and Fos, in cortical layers III and V. After 24 h recovery, we observed overshoot of transcriptional processes rather than a smooth return to homeostasis suggesting an oscillation of plasticity occurs during the transition to a new phase of neuronal regulation. These data elucidate critical molecular regulatory actions during and downstream of ketamine administration that may contribute to the unique drug actions of this anesthetic agent. These molecular investigations point to pathways linked to therapeutically useful attributes of ketamine.

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“…Here also, the expression was not restricted to the medial dorsal horn. The excitatory dynorphin neurons are of interest, as a transcriptomic study conducted in mice showed a unilateral upregulation of genes specifically in these neurons in the superficial laminae ipsilateral to the site of surgical incision or carrageenan inflammation 71 . Additionally, another study showed that excitatory dynorphin neurons are implicated in noxious heat-induced burn injury 72 .…”

Section: Discussionmentioning

confidence: 99%

Spatial, transcriptomic and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition

Arokiaraj

Kleyman

Chamessian

et al. 2022

Preprint

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SummaryThe spinal dorsal horn transforms incoming somatosensory information and transmits it supraspinally to generate modality-specific sensory percepts. The lack of an established framework for the molecular and cellular organization of the dorsal horn across species has greatly hampered delineating precisely how this region processes somatosensory information, including pain. Furthermore, the translation potential of the rodent work is unclear without data from higher order species. To fill these gaps, we performed single nucleus RNA-sequencing of Rhesus macaque dorsal horn and compared the results to a recently reported meta-analysis of mouse. Because dorsal horn laminae serve as a key organizing principle for function, we also determined the laminar location of each identified cell type. The work provides a comprehensive cross-species cellular and molecular database that will be critical for decoding the logic of dorsal horn somatosensory circuits and validating preclinical targets.

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The Persistent Pain Transcriptome: Identification of Cells and Molecules Activated by Hyperalgesia

Cited by 7 publications

References 157 publications

CRISPR/Cas9-Based Mutagenesis of Histone H3.1 in Spinal Dynorphinergic Neurons Attenuates Thermal Sensitivity in Mice

CRISPR/Cas9-Based Mutagenesis of Histone H3.1 in Spinal Dynorphinergic Neurons Attenuates Thermal Sensitivity in Mice

Transcriptional Activation, Deactivation and Rebound Patterns in Cortex, Hippocampus and Amygdala in Response to Ketamine Infusion in Rats

Spatial, transcriptomic and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition

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