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Article: MNK1 and MNK2 expression in the human dorsal root and trigeminal ganglion.

Shiers, Stephanie / Sahn, James J / Price, Theodore J

bioRxiv : the preprint server for biology

2023

Abstract: Mitogen activated protein kinase interacting kinases (MNK) 1 and 2 are serine/threonine protein kinases that play an important role in translation of mRNAs through their phosphorylation of the RNA 5â€™-cap binding protein, eukaryotic translation ... ...

Abstract	Mitogen activated protein kinase interacting kinases (MNK) 1 and 2 are serine/threonine protein kinases that play an important role in translation of mRNAs through their phosphorylation of the RNA 5â€™-cap binding protein, eukaryotic translation initiation factor (eIF) 4E. These kinases are downstream targets for mitogen activated protein kinases (MAPKs), extracellular activity regulated protein kinase (ERK) and p38. MNKs have been implicated in the sensitization of peripheral nociceptors of the dorsal root and trigeminal ganglion (DRG and TG) using transgenic mouse lines and through the use of specific inhibitors of MNK1 and MNK2. While specific knockout of the
Language	English
Publishing date	2023-01-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.04.522773
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Article ; Online: MNK1 and MNK2 Expression in the Human Dorsal Root and Trigeminal Ganglion.

Shiers, Stephanie / Sahn, James J / Price, Theodore J

Neuroscience

2023 Volume 515, Page(s) 96–107

Abstract: Mitogen activated protein kinase interacting kinases (MNK) 1 and 2 are serine/threonine protein kinases that play an important role in translation of mRNAs through their phosphorylation of the RNA 5'-cap binding protein, eukaryotic translation initiation ...

Abstract	Mitogen activated protein kinase interacting kinases (MNK) 1 and 2 are serine/threonine protein kinases that play an important role in translation of mRNAs through their phosphorylation of the RNA 5'-cap binding protein, eukaryotic translation initiation factor (eIF) 4E. These kinases are downstream targets for mitogen activated protein kinases (MAPKs), extracellular activity regulated protein kinase (ERK) and p38. MNKs have been implicated in the sensitization of peripheral nociceptors of the dorsal root and trigeminal ganglion (DRG and TG) using transgenic mouse lines and through the use of specific inhibitors of MNK1 and MNK2. While specific knockout of the Mknk1 gene suggests that it is the key isoform for regulation of nociceptor excitability and nociceptive behaviors in mice, both MKNK1 and MKNK2 genes are expressed in the DRG and TG of mice and humans based on RNA sequencing experiments. Single cell sequencing in mice suggests that Mknk1 and Mknk2 may be expressed in different populations of nociceptors. We sought to characterize mRNA expression in human DRG and TG (N = 3 ganglia for both DRG and TG) for both MNK1 and MNK2. Our results show that both genes are expressed by nearly all neurons in both human ganglia with expression in other cell types as well. Our findings provide evidence that MNK1 and MNK2 are expressed by human nociceptors of males and females and suggest that efforts to pharmacologically target MNKs for pain would likely be translatable due its conserved expression in both species.
MeSH term(s)	Animals ; Female ; Humans ; Male ; Mice ; Eukaryotic Initiation Factor-4E/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Spinal Nerve Roots/metabolism ; Trigeminal Ganglion/metabolism
Chemical Substances	Eukaryotic Initiation Factor-4E ; Intracellular Signaling Peptides and Proteins ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MKNK1 protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; MKNK2 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2023-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2023.01.039
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Article ; Online: Molecular, circuit, and anatomical changes in the prefrontal cortex in chronic pain.

Shiers, Stephanie / Price, Theodore J

Pain

2020 Volume 161, Issue 8, Page(s) 1726–1729

MeSH term(s)	Anxiety Disorders ; Chronic Pain ; Humans ; Prefrontal Cortex
Language	English
Publishing date	2020-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	193153-2
ISSN	1872-6623 ; 0304-3959
ISSN (online)	1872-6623
ISSN	0304-3959
DOI	10.1097/j.pain.0000000000001897
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Article ; Online: Neuroscience: A Male-Specific Pain Memory Mechanism.

Shiers, Stephanie / Price, Theodore J

Current biology : CB

2019 Volume 29, Issue 2, Page(s) R50–R52

Abstract: Memories of painful events protect us from danger. A new study demonstrates that, in both mice and humans, pain memories elicited by place conditioning are driven by spinal mechanisms, involve stress circuits and are surprisingly only found in males. ...

Abstract	Memories of painful events protect us from danger. A new study demonstrates that, in both mice and humans, pain memories elicited by place conditioning are driven by spinal mechanisms, involve stress circuits and are surprisingly only found in males.
MeSH term(s)	Animals ; Humans ; Male ; Memory ; Mice ; Neurosciences ; Pain
Language	English
Publishing date	2019-01-19
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2018.11.062
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Article ; Online: Quantitative differences in neuronal subpopulations between mouse and human dorsal root ganglia demonstrated with RNAscope in situ hybridization.

Shiers, Stephanie / Klein, Rebecca M / Price, Theodore J

Pain

2020 Volume 161, Issue 10, Page(s) 2410–2424

Abstract: Next-generation transcriptomics in combination with imaging-based approaches have emerged as powerful tools for the characterization of dorsal root ganglion (DRG) neuronal subpopulations. The mouse DRG has been well characterized by many independently ... ...

Abstract	Next-generation transcriptomics in combination with imaging-based approaches have emerged as powerful tools for the characterization of dorsal root ganglion (DRG) neuronal subpopulations. The mouse DRG has been well characterized by many independently conducted studies with convergent findings, but few studies have directly compared expression of population markers between mouse and human. This is important because of our increasing reliance on the mouse as a preclinical model for translational studies. Although calcitonin gene-related peptide (CGRP) and P2X purinergic ion channel type 3 receptor (P2X3R) have been used to define peptidergic and nonpeptidergic nociceptor subpopulations, respectively, in mouse DRG, these populations may be different in other species. To directly test this, as well as a host of other markers, we used multiplex RNAscope in situ hybridization to elucidate the distribution of a multitude of unique and classic neuronal mRNAs in peptidergic (CGRP-expressing) and nonpeptidergic (P2X3R-expressing) nociceptor subpopulations in mouse and human DRG. We found a large overlapping CGRP and P2X3R neuronal subpopulation in human, lumbar DRG that was not present in mouse. We also found differential expression in a variety of mRNAs for transient receptor potential channels, cholinergic receptors, potassium channels, sodium channels, and other markers/targets. These data offer insights into the spatial and functional organization of neuronal cell subpopulations in the rodent and human DRG and support the idea that sensory system organizational principles are likely different between both species.
MeSH term(s)	Animals ; Calcitonin Gene-Related Peptide/genetics ; Female ; Ganglia, Spinal ; Humans ; In Situ Hybridization ; Male ; Mice ; Middle Aged ; Neurons ; Nociceptors ; Young Adult
Chemical Substances	Calcitonin Gene-Related Peptide (JHB2QIZ69Z)
Language	English
Publishing date	2020-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	193153-2
ISSN	1872-6623 ; 0304-3959
ISSN (online)	1872-6623
ISSN	0304-3959
DOI	10.1097/j.pain.0000000000001973
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Article ; Online: Evaluation of calcium-sensitive adenylyl cyclase AC1 and AC8 mRNA expression in the anterior cingulate cortex of mice with spared nerve injury neuropathy.

Shiers, Stephanie / Elahi, Hajira / Hennen, Stephanie / Price, Theodore J

Neurobiology of pain (Cambridge, Mass.)

2021 Volume 11, Page(s) 100081

Abstract: The anterior cingulate cortex (ACC) is a critical region of the brain for the emotional and affective components of pain in rodents and humans. Hyperactivity in this region has been observed in neuropathic pain states in both patients and animal models ... ...

Abstract	The anterior cingulate cortex (ACC) is a critical region of the brain for the emotional and affective components of pain in rodents and humans. Hyperactivity in this region has been observed in neuropathic pain states in both patients and animal models and ablation of this region from cingulotomy, or inhibition with genetics or pharmacology can diminish pain and anxiety. Two adenylyl cyclases (AC), AC1 and AC8 play an important role in regulating nociception and anxiety-like behaviors through an action in the ACC, as genetic and pharmacological targeting of these enzymes reduces mechanical hypersensitivity and anxiety-like behavior, respectively. However, the distribution of these ACs in the ACC has not been studied in the context of neuropathic pain. To address this gap in knowledge, we conducted RNAscope
Language	English
Publishing date	2021-12-21
Publishing country	United States
Document type	Journal Article
ISSN	2452-073X
ISSN (online)	2452-073X
DOI	10.1016/j.ynpai.2021.100081
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Article: Na

Shiers, Stephanie / Funk, Geoffrey / Cervantes, Anna / Horton, Peter / Dussor, Gregory / Hennen, Stephanie / Price, Theodore J

bioRxiv : the preprint server for biology

2023

Abstract: ... ...

Abstract	Na
Language	English
Publishing date	2023-02-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.04.527110
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Article ; Online: Characterization of Fragile X Mental Retardation Protein expression in human nociceptors and their axonal projections to the spinal dorsal horn.

Mitchell, Molly E / Cook, Lauren C / Shiers, Stephanie / Tavares-Ferreira, Diana / Akopian, Armen N / Dussor, Gregory / Price, Theodore J

The Journal of comparative neurology

2023 Volume 531, Issue 7, Page(s) 814–835

Abstract: Fragile X Mental Retardation Protein (FMRP) regulates activity-dependent RNA localization and local translation to modulate synaptic plasticity throughout the central nervous system. Mutations in the FMR1 gene that hinder or ablate FMRP function cause ... ...

Abstract	Fragile X Mental Retardation Protein (FMRP) regulates activity-dependent RNA localization and local translation to modulate synaptic plasticity throughout the central nervous system. Mutations in the FMR1 gene that hinder or ablate FMRP function cause Fragile X Syndrome (FXS), a disorder associated with sensory processing dysfunction. FXS premutations are associated with increased FMRP expression and neurological impairments including sex dimorphic presentations of chronic pain. In mice, FMRP ablation causes dysregulated dorsal root ganglion (DRG) neuron excitability and synaptic vesicle exocytosis, spinal circuit activity, and decreased translation-dependent nociceptive sensitization. Activity-dependent, local translation is a key mechanism for enhancing primary nociceptor excitability that promotes pain in animals and humans. These works indicate that FMRP likely regulates nociception and pain at the level of the primary nociceptor or spinal cord. Therefore, we sought to better understand FMRP expression in the human DRG and spinal cord using immunostaining in organ donor tissues. We find that FMRP is highly expressed in DRG and spinal neuron subsets with substantia gelatinosa exhibiting the most abundant immunoreactivity in spinal synaptic fields. Here, it is expressed in nociceptor axons. FMRP puncta colocalized with Nav1.7 and TRPV1 receptor signals suggesting a pool of axoplasmic FMRP localizes to plasma membrane-associated loci in these branches. Interestingly, FMRP puncta exhibited notable colocalization with calcitonin gene-related peptide (CGRP) immunoreactivity selectively in female spinal cord. Our results support a regulatory role for FMRP in human nociceptor axons of the dorsal horn and implicate it in the sex dimorphic actions of CGRP signaling in nociceptive sensitization and chronic pain.
MeSH term(s)	Humans ; Animals ; Mice ; Female ; Fragile X Mental Retardation Protein/genetics ; Fragile X Mental Retardation Protein/metabolism ; Nociceptors/metabolism ; Chronic Pain ; Calcitonin Gene-Related Peptide/metabolism ; Axons/metabolism ; Fragile X Syndrome/genetics ; Spinal Cord Dorsal Horn/metabolism
Chemical Substances	Fragile X Mental Retardation Protein (139135-51-6) ; Calcitonin Gene-Related Peptide (JHB2QIZ69Z) ; FMR1 protein, human ; Fmr1 protein, mouse
Language	English
Publishing date	2023-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3086-7
ISSN	1096-9861 ; 0021-9967 ; 0092-7317
ISSN (online)	1096-9861
ISSN	0021-9967 ; 0092-7317
DOI	10.1002/cne.25463
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Article: Neural Mechanisms Responsible for Vagus Nerve Stimulation-Dependent Enhancement of Somatosensory Recovery.

Malley, Kaitlyn M / Ruiz, Andrea D / Darrow, Michael J / Danaphongse, Tanya / Shiers, Stephanie / Ahmad, Fatima N / Beltran, Clareth Mota / Stanislav, Benjamin T / Price, Theodore / Ii, Robert L Rennaker / Kilgard, Michael P / Hays, Seth A

Research square

2024

Abstract: Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) ... ...

Abstract	Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention.
Language	English
Publishing date	2024-01-29
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3873435/v1
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Article ; Online: Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain.

Yousuf, Muhammad Saad / Shiers, Stephanie I / Sahn, James J / Price, Theodore J

Pharmacological reviews

2020 Volume 73, Issue 1, Page(s) 59–88

Abstract: Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States ...

Abstract	Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase-interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders. SIGNIFICANCE STATEMENT: Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase-interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.
MeSH term(s)	Chronic Pain/drug therapy ; Humans ; Phosphorylation ; RNA, Messenger ; Signal Transduction
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2020-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	209898-2
ISSN	1521-0081 ; 0031-6997
ISSN (online)	1521-0081
ISSN	0031-6997
DOI	10.1124/pharmrev.120.000030
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