Comprehensive phenotyping of cutaneous afferents reveals early-onset alterations in nociceptor response properties, release of CGRP, and hindpaw edema following spinal cord injury

Eller, Olivia C.; Stair, Rena; Neal, Christopher; Rowe, Peter; Nelson-Brantley, Jennifer; Young, Erin E.; Baumbauer, Kyle M.

doi:10.1016/j.ynpai.2022.100097

Cited by 4 publications

(8 citation statements)

References 112 publications

(133 reference statements)

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“…One week following moderate thoracic contusion SCI in mice, nociceptors were identified to be hyperexcitable in skin-nerve preparations (lower activation thresholds and afterdischarges). These findings are in line with studies in cultured DRG neurons (31)(32)(33)(34) and confirm recent evidence in skin-nerve-DRG-spinal cord preparations taken 1 day post-injury in a moderate mouse contusion SCI model (29). Moreover, the observation of afterdischarges in nociceptors represents the likely correlate of prolonged hindpaw nocifensive behavior (licking, shaking, holding) in response to lighter von Frey hair filaments in SCI contused mice 7 days post-injury and goes beyond reflexive movements thus suggesting a supraspinal pain response.…”

Section: Nociceptor Hypersensitivity Is Observed In Sci Subjects Up T...supporting

confidence: 91%

“…This is supported by the absence of mechanoreceptor hyperexcitability in skin-nerve preparation 7 days after thoracic contusion SCI in mice. A recent publication investigating hyperexcitability in DRG in a skin-DRGspinal cord preparation 1 day after mouse contusion injury made the identical observation of absent mechanoreceptor hyperexcitability (29). Central branches of mechanoreceptors form the lemniscal tract, which reach from their entry point into the spinal cord below injury level all the way rostral across the spinal cord injury site.…”

Section: Nociceptor Hypersensitivity Is Observed In Sci Subjects Up T...mentioning

confidence: 94%

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Pre-Injury Mechanoreceptor Ablation Reduces Nociceptor-Driven Spinal Cord Injury-Induced Neuropathic Pain

Sliwinski

Heutehaus

Taberner

et al. 2022

Preprint

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Evidence from previous studies supports the concept that spinal cord injury (SCI) induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree nociceptors and mechanoreceptors contribute. Sensorimotor activation-based interventions (e.g. treadmill training) have been shown to reduce NP following experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. At the same time, nociceptors have been shown to become hyperexcitable early after SCI and peptidergic axons sprout into deeper laminae of the below injury level dorsal horn. The aim of the present study is to comprehensively understand the relative contribution of each pathway in respect to NP presentation in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B (TrkB) expressing mechanoreceptors before SCI mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. CGRP sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. Moreover, detection of hyperexcitability in nociceptors, not in mechanoreceptors, in skin-nerve preparations from contusion SCI mice 7 days after injury makes a significant direct contribution of mechanoreceptors to NP maintenance unlikely. SNS reporter mice allowing specific visualization of the entire nociceptor population confirmed significant sprouting of respective neurons into laminae III/IV as early as 5 days post-injury. Genetic ablation of SNS-Cre mice severely affected their overall health condition, which precluded them to undergo experimental SCI and subsequent further analysis. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors with consecutive peptidergic fiber sprouting in the dorsal horn are confirmed as the likely main driver of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.

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Section: Nociceptor Hypersensitivity Is Observed In Sci Subjects Up T...supporting

confidence: 91%

Section: Nociceptor Hypersensitivity Is Observed In Sci Subjects Up T...mentioning

confidence: 94%

Pre-Injury Mechanoreceptor Ablation Reduces Nociceptor-Driven Spinal Cord Injury-Induced Neuropathic Pain

Sliwinski

Heutehaus

Taberner

et al. 2022

Preprint

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“…Recent work from our lab and others, point to early engagement of peripheral mechanisms in the development of pain and dysfunction after SCI ( Eller et al, 2022 ), though NB has not been assessed explicitly. In line with this prior work, RNA sequencing (RNAseq) was conducted on the distal colon at both D1 and D7 post-SCI to identify high priority candidate genes and biological processes involved in initiation of NB early after SCI.…”

Section: Resultsmentioning

confidence: 99%

“…Recent evidence suggests that a pathological change in both the peripheral neurons and the peripheral tissues they innervate could contribute to the development of chronic pain and organ dysfunction. Eller et al 2022 reported findings of primary afferent hyperexcitability after thoracic SCI ( Eller et al, 2022 ). Not only were neurons in below-level dorsal root ganglia (DRG) hyperexcitable to mechanical stimulation of the hind paw skin, they displayed increased spontaneous activity and after-discharge, two pathological changes that may underlie nociceptor-driven chronic pain ( Yang et al, 2014 , Walters, 2012 , Bedi et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction

Willits,

Kader,

Eller

et al. 2024

Neurobiology of Pain

Self Cite

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“…These findings are in line with studies in cultured DRG neurons 5 , 7 , 8 , 50 and confirm recent evidence in skin-nerve-DRG-spinal cord preparations taken 1 day post-injury in a moderate mouse contusion SCI model. 15 Moreover, the observation of afterdischarges in nociceptors represents the likely correlate of prolonged hind paw nocifensive behavior (licking, shaking, and holding) in response to lighter von Frey hair filaments in SCI contused mice 7 days post-injury and goes beyond reflexive movements, thus suggesting a supraspinal pain response.…”

Section: Discussionmentioning

confidence: 99%

Contribution of mechanoreceptors to spinal cord injury–induced mechanical allodynia

Sliwinski,

Heutehaus,

Taberner

et al. 2023

Pain

View full text Add to dashboard Cite

Evidence from previous studies supports the concept that spinal cord injury (SCI)-induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree mechanoreceptors contribute. Sensorimotor activation-based interventions (eg, treadmill training) have been shown to reduce NP after experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. The aim of the present study was to understand the contribution of mechanoreceptors with respect to mechanical allodynia in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B expressing mechanoreceptors before SCI, mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. Peptidergic nociceptor sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. However, skin-nerve preparations of contusion SCI mice 7 days after injury yielded hyperexcitability in nociceptors, not in mechanoreceptors, which makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors seem to be the main drivers of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early-onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.

show abstract

Comprehensive phenotyping of cutaneous afferents reveals early-onset alterations in nociceptor response properties, release of CGRP, and hindpaw edema following spinal cord injury

Cited by 4 publications

References 112 publications

Pre-Injury Mechanoreceptor Ablation Reduces Nociceptor-Driven Spinal Cord Injury-Induced Neuropathic Pain

Pre-Injury Mechanoreceptor Ablation Reduces Nociceptor-Driven Spinal Cord Injury-Induced Neuropathic Pain

Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction

Contribution of mechanoreceptors to spinal cord injury–induced mechanical allodynia

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