Elevated levels of calcitonin gene-related peptide in upper spinal cord promotes sensitization of primary trigeminal nociceptive neurons

Cornelison, Lauren E.; Hawkins, Jordan; Durham, Paul L.

doi:10.1016/j.neuroscience.2016.10.013

Cited by 35 publications

(35 citation statements)

References 63 publications

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“…Recently, elevated levels of CGRP in the spinal trigeminal nucleus were shown to mediate increased expression of GFAP, a protein used as a biomarker of activated astrocytes (Cornelison et al, 2016). In agreement, findings from this study provide evidence that early life stress causes an increase in the expression of CGRP, and also GFAP.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence of bidirectional signaling within the trigeminal system may help to explain how elevated levels of CGRP in the spinal trigeminal nucleus, and subsequent activation of astrocytes, may promote sensitization of primary trigeminal neurons by facilitating neuron-glia communication and increased MAP kinase signaling (Cornelison et al, 2016). Similarly, results from this study provide evidence that exposure to prenatal and postnatal secondary traumatic stress can promote a sustained increase in P-ERK and P-p38 levels in primary nociceptive neurons and satellite glial cells within the trigeminal ganglion associated with peripheral sensitization in young adult animals.…”

Section: Discussionmentioning

confidence: 99%

“…Statistical analysis of immunostaining data was performed essentially as described previously (Cornelison et al, 2016; Hawkins et al, 2015; Koop et al, 2017). The relative fluorescent staining intensity in spinal cord tissue was determined by measuring the grayscale intensity from four regions, in laminae I–III, of the medullary dorsal horn.…”

Section: Methodsmentioning

confidence: 99%

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Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

et al. 2018

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The pathology of migraine, a common neurological disease, involves sensitization and activation of trigeminal nociceptive neurons to promote hyperalgesia and allodynia during an attack. Migraineurs often exhibit characteristics of a hyperexcitable or hypervigilant nervous system. One of the primary reported risk factors for development of a hyperexcitable trigeminal system is chronic, unmanaged stress and anxiety. While primary traumatic stress is a commonly cited risk factor for many pain conditions, exposure to secondary traumatic stress early in life is also thought to be a contributing risk factor. The goal of this study was to investigate cellular changes within the spinal trigeminal nucleus and trigeminal ganglion mediated by secondary traumatic stress. Male Sprague Dawley rats (sender) were subjected to forced swim testing (primary traumatic stress) and were then housed in close visual, olfactory, and auditory proximity to the breeding male and female rats, pregnant female rats, or female rats and their nursing offspring (all receivers). In response to secondary stress, levels of calcitonin gene-related peptide, active forms of the mitogen activated protein kinases ERK, JNK, and p38, and astrocyte expression of glial fibrillary acidic protein were significantly elevated in the spinal trigeminal nucleus in day 45 offspring when compared to naïve offspring. In addition, increased nuclear expression of ERK and p38 was observed in trigeminal ganglion neurons. Our results demonstrate that secondary traumatic stress promotes cellular events associated with prolonged trigeminal sensitization in the offspring, and provides a mechanism of how early life stress may function as a risk factor for migraine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

et al. 2018

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“…Translocation of p-ERK into neuronal nuclei is associated with increased expression of pro-inflammatory proteins including CGRP and cytokines that are known to promote peripheral nociceptor sensitization (51–53). Recent findings provide evidence of bidirectional signaling in the trigeminal system in which intrathecal administration of CGRP caused increased nuclear localization of p-ERK in the ganglion and increased neuron-satellite glial cell coupling (54). Thus, blocking CFA-induced PKA activation in the STN, which resulted in lower CGRP levels in the spinal cord, likely mediates in part the observed decrease in p-ERK, and hence the inhibition of trigeminal nociception in response to mechanical stimulation.…”

Section: Discussionmentioning

confidence: 99%

Central Role of Protein Kinase A in Promoting Trigeminal Nociception in an In Vivo Model of Temporomandibular Disorders

Koop¹,

Hawkins²,

Cornelison³

et al. 2017

J Oral Facial Pain Headache

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Aims To investigate cellular changes in the spinal trigeminal nucleus (STN) and trigeminal ganglion associated with trigeminal nociception mediated by inflammation in the temporomandibular joint (TMJ) capsule. Methods Sprague Dawley rats (n=86) were utilized to investigate cellular and behavioral responses to prolonged TMJ inflammation caused by bilateral injection of complete Freund’s adjuvant (CFA) in the capsule. To investigate the cellular effects of protein kinase A (PKA) in the STN, rats were injected intrathecally with the selective PKA inhibitor KT5720 prior to injection of CFA into both TMJ capsules. Levels of calcitonin gene-related peptide (CGRP), active PKA, and ionized calcium-binding adapter molecule 1(Iba1) in the STN and expression of phosphorylated ERK (p-ERK) in the trigeminal ganglion were determined by immunohistochemistry (n ≥ 3). Nocifensive head withdrawal responses to mechanical stimulation of the cutaneous tissue over the TMJ were monitored following CFA injection in the absence or presence of KT5720 (n = 7). Statistical analysis was performed using parametric ANOVA tests. Results Intrathecal injection of KT5720 significantly inhibited the stimulatory effect of CFA on levels of CGRP, PKA, and the microglial protein Iba1 in the STN. In addition, administration of KT5720 decreased the average number of CFA-induced nocifensive withdrawal responses to mechanical stimulation and the CFA-mediated increase in p-ERK expression in the ganglion. Conclusion These findings provide evidence that elevated PKA activity in the STN promotes cellular events temporally associated with trigeminal nociception caused by prolonged TMJ inflammation.

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“…The same was confirmed in the mouse embryos (Wang et al, 2017) indicating CGRP as marker of viscerosensory pathways (Benarroch, 2011) for the small‐diameter unmyelinated nociceptive peptidergic neurons (Marmigère and Ernfors, 2007). Higher levels of CGRP facilitate trigeminal ways of sensitizations of primary nociceptive neurons in upper SC (Cornelison et al, 2016; Miller et al, 2016). Since CGRP was also found in motorneurons (Marti et al, 1987; Harmann et al, 1988; Torres‐Da‐Silva et al, 2016), it was proposed that CGRP can be involved in axonal elongation as well in synapsis formation (Kim et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Time course and expression pattern of the neuronal markers in the developing human spinal cord

Restović

Bočina

Vukojević

et al. 2019

Intl J of Devlp Neuroscience

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The aim of this study was to examine the spatio‐temporal appearance of different neuronal cell subtypes by analyzing expression patterns of several neuronal markers (calretinin, neurofilament 200 (NF200), vanilloid receptor 1(VR1) and calcitonin gene‐related peptide (CGRP)) of the embryonic human spinal cord (SC). Developing human SCs from 11 human conceptuses beetwen 5–10 developmental weeks (DW) were examined by light and electron microscopy and immunofluorescence. Light and electron microscopy revealed different embryonic stages of recognizable structure of the SC. NF200, CGRP and VR1 positive cells were observed in SCs during 5th–6th DW. NF200 was predominantly expressed in the ventral part, indicating presence of motoneurons. As development advanced, NF200 was mainly expressed in the marginal zone. Expression of CGRP was intense during all of the investigated periods, predominantly during the 5th–6th DW pointing to neural sensory differentiation, as opposed to the last DW when reduced expression of CGRP in the marginal layer indicated the terminations of the sensory afferents. Expression of VR1 was highest in the intermediate zone, at the beginning and at the end of the investigated periods, pointing to VR1 spatial pattern in the visceral afferents in the grey matter, while the first signs of calretinin were found in the 9th–10th DW ventrally. Delineating the relationships between factors involved in processes of neuronal differentiation as well as spatial and temporal arrangement of SC interrelated neurons can provide a useful information about normal SC development as well as the insight in possible causes of anomalies and disorders during embryonic life.

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Elevated levels of calcitonin gene-related peptide in upper spinal cord promotes sensitization of primary trigeminal nociceptive neurons

Cited by 35 publications

References 63 publications

Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

Central Role of Protein Kinase A in Promoting Trigeminal Nociception in an In Vivo Model of Temporomandibular Disorders

Time course and expression pattern of the neuronal markers in the developing human spinal cord

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