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

Megat, Salim; Ray, Pradipta; Tavares‐Ferreira, Diana; Moy, Jamie K.; Sankaranarayanan, Ishwarya; Wanghzou, Andi; Lou, Tzu-Fang; Barragán-Iglesias, Paulino; Campbell, Zachary T.; Dussor, Gregory; Price, Theodore J.

doi:10.1523/jneurosci.2663-18.2019

Cited by 78 publications

(72 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Conversely, the trigeminal ganglion had RNAs encoding vasopressin, oxytocin and GABA receptor subunits. A similar RNAseq study focusing on RNAs being actively translated revealed that the trigeminal ganglion has greater expression of genes in the PI3K-mTORC1 pathway, while inhibitors of the pathway were more prominent in the dorsal root ganglion (Megat et al 2019). Enhanced expression of PI3K-mTORC1 pathway genes in the trigeminal ganglion was also confirmed at the protein level.…”

Section: Comparison Of Trigeminal and Dorsal Root Ganglia Sensory Neumentioning

confidence: 79%

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

2020

View full text Add to dashboard Cite

The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons are surrounded by satellite glial cells and the axons are wrapped by myelinating and non-myelinating Schwann cells. Trigeminal neurons express various neuropeptides, most notably, calcitonin generelated peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP). Two types of CGRP receptors are expressed in neurons and satellite glia. A variety of other signal molecules like ATP, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion neurons and signal to neighboring neurons or satellite glial cells, which can signal back to neurons with same or other mediators. This potential cross-talk of signals involves intracellular mechanisms, including gene expression, that can modulate mediators of sensory information, such as neuropeptides, receptors, and neurotrophic factors. From the ganglia cell bodies, which are outside the blood-brain barrier, the mediators are further distributed to peripheral sites and/or to the spinal trigeminal nucleus in the brainstem, where they can affect neural transmission. A major question is how the sensory neurons in the trigeminal ganglion differ from those in the dorsal root ganglion. Despite their functional overlap, there are distinct differences in their ontogeny, gene expression, signaling pathways, and responses to anti-migraine drugs. Consequently, drugs that modulate cross-talk in the trigeminal ganglion can modulate both peripheral and central sensitization, which may potentially be distinct from sensitization mediated in the dorsal root ganglion.

show abstract

Section: Comparison Of Trigeminal and Dorsal Root Ganglia Sensory Neumentioning

confidence: 79%

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

2020

View full text Add to dashboard Cite

show abstract

“…We also observed non-labeled (WGA-488) cells and dead cells (propidium iodide, PI+), to be excluded from cell sorting and analysis ( Figure 2B). As expected, a significant number of viable small nociceptor cells were excluded in this analytical approach, to avoid including RNAs from non-nociceptor cells or attached fragments of dead cells (examples in Figure 2C; Thakur et al, 2014;Lopes et al, 2017;Megat et al, 2019).…”

Section: Confirmation Of Cell Population Specific Labeling Of Cutaneomentioning

confidence: 99%

“…To gain further insight into differentially regulated genes in our isolated population of neurons, we compared our dataset with similar studies on isolated DRGs from publicly available datasets which focused on nociceptors (expressing Na v 1.8) or DRG collected from the same lumbar spinal level (L2-L6; Figure 6; Thakur et al, 2014;Usoskin et al, 2015;Hu et al, 2016;Megat et al, 2019). Unsupervised hierarchical clustering of the top 260 genes revealed that a large number of genes display distinct patterns of expression dependent upon the technique used: isolated neurons from all DRG by translating ribosome affinity purification (TRAP) using the Na v 1.8 Cre mouse (Megat et al, 2019); single-cell isolation from L3 to L5 DRG (Hu et al, 2016); single-cell isolation from L4-L6 DRG (Usoskin et al, 2015); and magnetic cell sorting (MACS) using the Na v 1.8 TdTomato mouse (Thakur et al, 2014; Figure 6A). We found that, while our cutaneous nociceptor-enriched population clustered most closely with the datasets of both TRAP sorted and unsorted DRG from Megat et al (2019), our isolated population was characterized by its own unique dataset.…”

Section: Backlabeled Facs-sorted Cutaneous Cell Transcriptome Is Distmentioning

confidence: 99%

Transcriptional Profiling of Non-injured Nociceptors After Spinal Cord Injury Reveals Diverse Molecular Changes

Yasko

Moss

Mains

2019

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently, patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons below the injury level may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15 g for 1 min. Alterations in gene expression produce long-term sensory changes, therefore, we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescenceactivated cell sorting (FACS). RNA was extracted from sorted sensory neurons of naïve, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed, we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain.

show abstract

“…E-2-dependent connections between translational control of the Suppressor of Cytokine Signaling (SOCS) and mTOR phosphorylation (Augusto et al, 2010) or regulation of Rheb signaling (Pochynyuk et al, 2006) have been proposed (Matthews et al, 2005; Arbocco et al, 2016). These signaling pathways also play key roles in the excitability of nociceptors (Moy et al, 2017; Khoutorsky and Price, 2018; Megat et al, 2019b; Megat et al, 2019a) and may play a more prominent role in the maintenance of persistent nociceptor plasticity in females than males.…”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Paige¹,

Barba-Escobedo

Mecklenburg

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.Significance StatementFemales are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice – where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.

show abstract

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

Cited by 78 publications

References 63 publications

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

Transcriptional Profiling of Non-injured Nociceptors After Spinal Cord Injury Reveals Diverse Molecular Changes

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Contact Info

Product

Resources

About