An Anatomical and Immunohistochemical Characterization of Afferents Innervating the C6–C7 Facet Joint After Painful Joint Loading in the Rat

Kras, Jeffrey V.; Tanaka, Kosuke; Gilliland, Taylor; Winkelstein, Beth A.

doi:10.1097/brs.0b013e318285b5bb

Cited by 20 publications

(32 citation statements)

References 43 publications

(73 reference statements)

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“…For example, neck pain, a common musculoskeletal disorder, can originate from spinal ligaments [6]. In particular, the facet capsular ligament (FCL) that encloses the spinal facet joints is a common source of pain due to neck trauma [7][8][9]. Biomechanical and neurophysiological studies in animal models have shown that excessive FCL loading that produces nonphysiologic strains also induces damage to the collagen network and axons of innervating neurons, persistent afferent firing, spinal neuronal hypersensitivity, and altered neurotransmitter expression, as well as pain [7,[10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction

Zhang

Stablow

Shenoy

et al. 2016

Journal of Biomechanical Engineering

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Excessive loading of ligaments can activate the neural afferents that innervate the collagenous tissue, leading to a host of pathologies including pain. An integrated experimental and modeling approach was used to define the responses of neurons and the surrounding collagen fibers to the ligamentous matrix loading and to begin to understand how macroscopic deformation is translated to neuronal loading and signaling. A neuron-collagen construct (NCC) developed to mimic innervation of collagenous tissue underwent tension to strains simulating nonpainful (8%) or painful ligament loading (16%). Both neuronal phosphorylation of extracellular signal-regulated kinase (ERK), which is related to neuroplasticity (R 2 ! 0.041; p 0.0171) and neuronal aspect ratio (AR) (R 2 ! 0.250; p < 0.0001), were significantly correlated with tissue-level strains. As NCC strains increased during a slowly applied loading (1%/s), a "switchlike" fiber realignment response was detected with collagen reorganization occurring only above a transition point of 11.3% strain. A finite-element based discrete fiber network (DFN) model predicted that at bulk strains above the transition point, heterogeneous fiber strains were both tensile and compressive and increased, with strains in some fibers along the loading direction exceeding the applied bulk strain. The transition point identified for changes in collagen fiber realignment was consistent with the measured strain threshold (11.7% with a 95% confidence interval of 10.2-13.4%) for elevating ERK phosphorylation after loading. As with collagen fiber realignment, the greatest degree of neuronal reorientation toward the loading direction was observed at the NCC distraction corresponding to painful loading. Because activation of neuronal ERK occurred only at strains that produced evident collagen fiber realignment, findings suggest that tissue strain-induced changes in the micromechanical environment, especially altered local collagen fiber kinematics, may be associated with mechanotransduction signaling in neurons.

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Section: Introductionmentioning

confidence: 99%

Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction

Zhang

Stablow

Shenoy

et al. 2016

Journal of Biomechanical Engineering

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“…Neurons expressing the NK1 receptor (NK1R) were ablated using a targeted SP conjugate of the neurotoxin saporin, [Sar 9 ,Met(O 2 ) 11 ]-substance P-saporin (SSP-Sap) (Advanced Targeting Systems), via intra-articular injection as described previously [10]: 100ng of SSP-Sap dissolved in PBS (5µL) and injected into the bilateral C6/C7 facet joints (n=20). Non-targeted saporin (100ng) was injected in separate rats as controls (Blank-Sap n=16).…”

Section: Methodsmentioning

confidence: 99%

“…Forepaw mechanical withdrawal thresholds were quantified for all rats using customary methods [10,24]. Rats were acclimated to the testing environment for 20 minutes prior to application of an ascending series of von Frey filaments to each forepaw; the lower of two consecutive filaments eliciting emphatic lifting of the forepaw was taken as the threshold.…”

Section: Methodsmentioning

confidence: 99%

“…Fourteen days later under inhalation isoflurane anesthesia, rats underwent either a facet joint distraction (FJD) (SSP-Sap+FJD n=7; Blank-Sap+FJD n=7) or sham (SSP-Sap+sham n=4), as previously described [10,24]. A loading device distracted the bilateral C6/C7 facet joints by displacing the C6 vertebra rostrally and holding C7 fixed.…”

Section: Methodsmentioning

confidence: 99%

“…Proprioceptors and nociceptors innervating the capsular ligament respond to its stretch [4,5,6]. Both peptidergic (expressing neuropeptides like substance P (SP)) and non-peptidergic (binding isolectin B4 (IB4)) primary afferents innervate the facet joint [7,8,9,10]. Clinically and experimentally, anesthetic nerve blocks demonstrate that joint afferents contribute to facet-mediated pain [11,12,13].…”

Section: Introductionmentioning

confidence: 99%

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Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents

Kras

Weisshaar

Pall

et al. 2015

Neuroscience Letters

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Non-physiological stretch of the cervical facet joint’s capsular ligament induces persistent behavioral hypersensitivity and spinal neuronal hyperexcitability via an intra-articular NGF-dependent mechanism. Although that ligament is innervated by nociceptors, it is unknown if a subpopulation is exclusively responsible for the behavioral and spinal neuronal responses to intra-articular NGF and/or facet joint injury. This study ablated joint afferents using the neurotoxin saporin targeted to neurons involved in either peptidergic ([Sar9,Met(O2)11]-substance P-saporin (SSP-Sap)) or non-peptidergic (isolectin B4-saporin (IB4-Sap)) signaling to investigate the contributions of those neuronal populations to facet-mediated pain. SSP-Sap, but not IB4-Sap, injected into the bilateral C6/C7 facet joints 14 days prior to an intra-articular NGF injection prevents NGF-induced mechanical and thermal hypersensitivity in the forepaws. Similarly, only SSP-Sap prevents the increase in mechanical forepaw stimulation-induced firing of spinal neurons after intra-articular NGF. In addition, intra-articular SSP-Sap prevents both behavioral hypersensitivity and upregulation of NGF in the dorsal root ganglion after a facet joint distraction that normally induces pain. These findings collectively suggest that disruption of peptidergic signaling within the joint may be a potential treatment for facet pain, as well as other painful joint conditions associated with elevated NGF, such as osteoarthritis.

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Brain-derived neurotrophic factor is upregulated in the cervical dorsal root ganglia and spinal cord and contributes to the maintenance of pain from facet joint injury in the rat

Kras

Weisshaar

Quindlen

et al. 2013

Journal of Neuroscience Research

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The facet joint is commonly associated with neck and low back pain and is susceptible to loading-induced injury. Although tensile loading of the cervical facet joint has been associated with inflammation and neuronal hyperexcitability, the mechanisms of joint loading-induced pain remain unknown. Altered brain-derived neurotrophic factor (BDNF) levels are associated with a host of painful conditions, but the role of BDNF in loading-induced joint pain remains undefined. Separate groups of rats underwent a painful cervical facet joint distraction or a sham procedure. Bilateral forepaw mechanical hypersensitivity was assessed and BDNF mRNA and protein levels were quantified in the dorsal root ganglion (DRG) and spinal cord at days 1 and 7. Facet joint distraction induced significant (P < 0.001) mechanical hypersensitivity at both time points. Painful joint distraction did not alter BDNF mRNA in the DRG compared with sham levels but did significantly increase (P < 0.016) BDNF protein expression over sham in the DRG at day 7. Painful distraction also significantly increased BDNF mRNA (P = 0.031) and protein expression (P = 0.047) over sham responses in the spinal cord at day 7. In a separate study, intrathecal administration of the BDNF-sequestering molecule trkB-Fc on day 5 after injury partially attenuated behavioral sensitivity after joint distraction and reduced pERK in the spinal cord at day 7 (P < 0.045). Changes in BDNF after painful facet joint injury and the effect of spinal BDNF sequestration in partially reducing pain suggest that BDNF signaling contributes to the maintenance of loading-induced facet pain but that additional cellular responses are also likely involved.

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An Anatomical and Immunohistochemical Characterization of Afferents Innervating the C6–C7 Facet Joint After Painful Joint Loading in the Rat

Cited by 20 publications

References 43 publications

Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction

Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction

Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents

Brain-derived neurotrophic factor is upregulated in the cervical dorsal root ganglia and spinal cord and contributes to the maintenance of pain from facet joint injury in the rat

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