Manual therapy and exercise effects on inflammatory cytokines: a narrative overview.

Background: Matching disease and treatment mechanisms is a goal of the Precision Medicine Initiative. Pro- and anti-inflammatory cytokines (e.g., Tumor Necrosis Factor-alpha, Transforming Growth Factor-beta, and Interleukin-2, 10, and 12) have gained a significant amount of interest in their potential role in persistent pain for musculoskeletal (MSK) conditions. Manual therapy (MT) and exercise are two guideline-recommended approaches for treating MSK conditions. The objective of this narrative overview was to investigate of the effects of MT and exercise on pro- and anti-inflammatory cytokines and determine the factors that lead to variability in results. Methods: Two reviewers evaluated the direction and variabilities of MT and exercise literature. A red, yellow, and green light scoring system was used to define consistencies. Results: Consistencies in responses were seen with acute and chronic exercise and both pro- and anti-inflammatory cytokines. Chronic exercise is associated with a consistent shift towards a more anti-inflammatory cytokine profile (Transforming Growth Factor-beta, and Interleukin-2 and 13, whereas acute bouts of intense exercise can transiently increase pro-inflammatory cytokine levels. The influence of MT on cytokines was less commonly studied and yielded more variable results. Conclusion: Variability in findings is likely related to the subject and their baseline condition or disease, when measurement occurs, and the exercise intensity, duration, and an individual's overall health and fitness.

Cervical facet capsular ligament mechanics: Estimations based on subject-specific anatomy and kinematics.

Background: To understand the facet capsular ligament's (FCL) role in cervical spine mechanics, the interactions between the FCL and other spinal components must be examined. One approach is to develop a subject-specific finite element (FE) model of the lower cervical spine, simulating the motion segments and their components' behaviors under physiological loading conditions. This approach can be particularly attractive when a patient's anatomical and kinematic data are available. Methods: We developed and demonstrated methodology to create 3D subject-specific models of the lower cervical spine, with a focus on facet capsular ligament biomechanics. Displacement-controlled boundary conditions were applied to the vertebrae using kinematics extracted from biplane videoradiography during planar head motions, including axial rotation, lateral bending, and flexion-extension. The FCL geometries were generated by fitting a surface over the estimated ligament-bone attachment regions. The fiber structure and material characteristics of the ligament tissue were extracted from available human cervical FCL data. The method was demonstrated by application to the cervical geometry and kinematics of a healthy 23-year-old female subject. Results: FCL strain within the resulting subject-specific model were subsequently compared to models with generic: (1) geometry, (2) kinematics, and (3) material properties to assess the effect of model specificity. Asymmetry in both the kinematics and the anatomy led to asymmetry in strain fields, highlighting the importance of patient-specific models. We also found that the calculated strain field was largely independent of constitutive model and driven by vertebrae morphology and motion, but the stress field showed more constitutive-equation-dependence, as would be expected given the highly constrained motion of cervical FCLs. Conclusions: The current study provides a methodology to create a subject-specific model of the cervical spine that can be used to investigate various clinical questions by coupling experimental kinematics with multiscale computational models.

Characterization of the L4/L5 rat facet capsular ligament macromechanical and microstructural responses to tensile failure loading.

Low back pain is a prevalent condition that affects the global population. The lumbar facet capsular ligament is a source of pain since the collagenous tissue of the ligament is innervated with sensory neurons that deform with the capsule's stretch. Regional differences in the microstructural and macrostructural anatomy of the spinal facets affect its capsule's mechanical behavior. Although there are many studies of the cervical facet in human and rodent models, the lumbar capsular ligament's multiscale behavior is less well-defined. This study characterizes the macroscale and fiber-scale changes of the rat lumbar facet capsule during tensile failure loading. An integrated polarized light imaging setup captured local fiber alignment during 0.08 mm/s distraction of 7 lumbar facets. Force, displacement, strain, and circular variance were measured at several points along the failure curve: the first instance when the local collagen fiber network realigns differentially (anomalous realignment), yield, the first peak in force corresponding to the capsule's first failure, and peak force, defined as ultimate rupture. Those outcomes were compared across events. While each of force, displacement, and average maximum principal strain increased with applied tension, so did the circular variance of the collagen, suggesting that the fibers were becoming more disorganized. From the fiber alignment maps collected at each mechanical event, the number of anomalous realignment events were counted and found to increase dramatically with loading. The increased collagen disorganization and increasing regions of such disorganization in the facet capsule during loading can provide insights about how loading to the ligament afferent nerves may be activated and thereby produce pain.

Intra-articular MMP-1 in the spinal facet joint induces sustained pain and neuronal dysregulation in the DRG and spinal cord, and alters ligament kinematics under tensile loading.

Chronic joint pain is a major healthcare challenge with a staggering socioeconomic burden. Pain from synovial joints is mediated by the innervated collagenous capsular ligament that surrounds the joint and encodes nociceptive signals. The interstitial collagenase MMP-1 is elevated in painful joint pathologies and has many roles in collagen regulation and signal transduction. Yet, the role of MMP-1 in mediating nociception in painful joints remains poorly understood. The goal of this study was to determine whether exogenous intra-articular MMP-1 induces pain in the spinal facet joint and to investigate effects of MMP-1 on mediating the capsular ligament's collagen network, biomechanical response, and neuronal regulation. Intra-articular MMP-1 was administered into the cervical C6/C7 facet joints of rats. Mechanical hyperalgesia quantified behavioral sensitivity before, and for 28 days after, injection. On day 28, joint tissue structure was assessed using histology. Multiscale ligament kinematics were defined under tensile loading along with microstructural changes in the collagen network. The amount of degraded collagen in ligaments was quantified and substance P expression assayed in neural tissue since it is a regulatory of nociceptive signaling. Intra-articular MMP-1 induces behavioral sensitivity that is sustained for 28 days (p < 0.01), absent any significant effects on the structure of joint tissues. Yet, there are changes in the ligament's biomechanical and microstructural behavior under load. Ligaments from joints injected with MMP-1 exhibit greater displacement at yield (p = 0.04) and a step-like increase in the number of anomalous reorganization events of the collagen fibers during loading (p ≤ 0.02). Collagen hybridizing peptide, a metric of damaged collagen, is positively correlated with the spread of collagen fibers in the unloaded state after MMP-1 (p = 0.01) and that correlation is maintained throughout the sub-failure regime (p ≤ 0.03). MMP-1 injection increases substance P expression in dorsal root ganglia (p < 0.01) and spinal cord (p < 0.01) neurons. These findings suggest that MMP-1 is a likely mediator of neuronal signaling in joint pain and that MMP-1 presence in the joint space may predispose the capsular ligament to altered responses to loading. MMP-1-mediated pathways may be relevant targets for treating degenerative joint pain in cases with subtle or no evidence of structural degeneration.

Inhibiting the ß1integrin subunit increases the strain threshold for neuronal dysfunction under tensile loading in collagen gels mimicking innervated ligaments.

Stretch injury of the facet capsular ligament is a cause of neck pain, inducing axonal injury, neuronal hyperexcitability, and upregulation of pain neuromodulators. Although thresholds for pain and collagen reorganization have been defined and integrins can modulate pain signaling with joint trauma, little is known about the role of integrin signaling in neuronal dysfunction from tensile loading of the innervated capsular ligament. Using a well-characterized biomimetic collagen gel model of the capsular ligament's microstructure and innervation, this study evaluated extrasynpatic expression of N-Methyl-D-Aspartate receptor subtype 2B (NR2B) as a measure of neuronal dysfunction following tensile loading and determined mechanical thresholds for its upregulation in primary sensory neurons, with and without integrin inhibition. Collagen gels with dissociated dorsal root ganglion neurons (n = 16) were fabricated; a subset of gels (n = 8) was treated with the ß1 integrin subunit inhibitor, TC-I15. Gels were stretched to failure in tension and then immunolabeled for axonal NR2B. Inhibiting the integrin subunit does not change the failure force (p = 0.12) or displacement (p = 0.44) but does reduce expression of the ß1 subunit by 41% (p < 0.001) and decrease axonal NR2B expression after stretch (p = 0.018). Logistic regressions estimating the maximum principal strain threshold for neuronal dysfunction as evaluated by Analysis of Covariance determine that integrin inhibition increases (p = 0.029) the 50th percentile strain threshold (7.1%) above the threshold for upregulation in untreated gels (6.2%). These results suggest that integrin contributes to stretch-induced neuronal dysfunction via neuron-integrin-collagen interactions.

MMPs in tissues retrieved during surgery from patients with TMJ disorders relate to pain more than to radiological damage score.

Orofacial pain is among the most common chronic pain conditions and can result from temporomandibular disorders (TMDs) of the temporomandibular joint (TMJ). Matrix metalloproteinases (MMPs) drive degeneration of TMJ tissues and likely mediate pain in TMJ disorders given their role in nociception. However, few studies have assessed MMPs in the TMJ innervated tissues nor in the context of pain. This study defined the extent of MMP-1, MMP-9, and MMP-2 in TMJ tissues from patients undergoing total joint replacement (TJR) or arthroplasty discectomy for painful TMJ disorders. Protein expression was probed by Western blot in TMJ disc and capsular ligaments taken during TJR (n = 6) or discectomy (n = 3) for osteoarthritis or internal derangement in an IRB-approved study. Pro- and active MMP-1, active MMP-9, and pro- and active MMP-2 are detectable. MMP-1 and MMP-9 correlate positively to each other (Kendall's τ = 0.63; p = 0.01), strengthening the hypothesis that they are mechanistically related in regulatory cascades. Active MMP-1 and active MMP-9 correlate positively with self-reported pain scores (τ ≥ 0.51; p ≤ 0.04), suggesting their involvement in peripheral nociception. Overall, neither MMPs nor pain correlate with the functional vertical opening of the jaw. MMP-1 varies with the observed stage of degeneration during surgery (p = 0.04). Neither overall MMPs nor pain correlate with the overall magnetic resonance imaging scores, corroborating the longstanding, but confounding, clinical observation that pain and radiological evidence of joint damage are not always related. Clinical significance: These findings suggest that MMPs mediate pain in innervated soft tissues and may be targets for diagnosing disease stage and treatments in painful TMJ disorders.

Painful temporomandibular joint overloading induces structural remodeling in the pericellular matrix of that joint's chondrocytes.

Mechanical stress to the temporomandibular joint (TMJ) is an important factor in cartilage degeneration, with both clinical and preclinical studies suggesting that repeated TMJ overloading could contribute to pain, inflammation, and/or structural damage in the joint. However, the relationship between pain severity and early signs of cartilage matrix microstructural dysregulation is not understood, limiting the advancement of diagnoses and treatments for temporomandibular joint-osteoarthritis (TMJ-OA). Changes in the pericellular matrix (PCM) surrounding chondrocytes may be early indicators of OA. A rat model of TMJ pain induced by repeated jaw loading (1 h/day for 7 days) was used to compare the extent of PCM modulation for different loading magnitudes with distinct pain profiles (3.5N-persistent pain, 2N-resolving pain, or unloaded controls-no pain) and macrostructural changes previously indicated by Mankin scoring. Expression of PCM structural molecules, collagen VI and aggrecan NITEGE neo-epitope, were evaluated at Day 15 by immunohistochemistry within TMJ fibrocartilage and compared between pain conditions. Pericellular collagen VI levels increased at Day 15 in both the 2N (p = 0.003) and 3.5N (p = 0.042) conditions compared to unloaded controls. PCM width expanded to a similar extent for both loading conditions at Day 15 (2N, p < 0.001; 3.5N, p = 0.002). Neo-epitope expression increased in the 3.5N group over levels in the 2N group (p = 0.041), indicating pericellular changes that were not identified in the same groups by Mankin scoring of the pericellular region. Although remodeling occurs in both pain conditions, the presence of pericellular catabolic neo-epitopes may be involved in the macrostructural changes and behavioral sensitivity observed in persistent TMJ pain.

Inhibiting spinal secretory phospholipase A2 after painful nerve root injury attenuates established pain and spinal neuronal hyperexcitability by altering spinal glutamatergic signaling.

Neuropathic injury is accompanied by chronic inflammation contributing to the onset and maintenance of pain after an initial insult. In addition to their roles in promoting immune cell activation, inflammatory mediators like secretory phospholipase A2 (sPLA2) modulate nociceptive and excitatory neuronal signaling during the initiation of pain through hydrolytic activity. Despite having a known role in glial activation and cytokine release, it is unknown if sPLA2 contributes to the maintenance of painful neuropathy and spinal hyperexcitability later after neural injury. Using a well-established model of painful nerve root compression, this study investigated if inhibiting spinal sPLA2 7 days after painful injury modulates the behavioral sensitivity and/or spinal dorsal horn excitability that is typically evident. The effects of sPLA2 inhibition on altered spinal glutamatergic signaling was also probed by measuring spinal intracellular glutamate levels and spinal glutamate transporter (GLAST and GLT1) and receptor (mGluR5, GluR1, and NR1) expression. Spinal sPLA2 inhibition at day 7 abolishes behavioral sensitivity, reduces both evoked and spontaneous neuronal firing in the spinal cord, and restores the distribution of neuronal phenotypes to those of control conditions. Inhibiting spinal sPLA2 also increases intracellular glutamate concentrations and restores spinal expression of GLAST, GLT1, mGluR5, and GluR1 to uninjured expression with no effect on NR1. These findings establish a role for spinal sPLA2 in maintaining pain and central sensitization after neural injury and suggest this may be via exacerbating glutamate excitotoxicity in the spinal cord.

Local tissue heterogeneity may modulate neuronal responses via altered axon strain fields: insights about innervated joint capsules from a computational model.

In innervated collagenous tissues, tissue scale loading may contribute to joint pain by transmitting force through collagen fibers to the embedded mechanosensitive axons. However, the highly heterogeneous collagen structures of native tissues make understanding this relationship challenging. Recently, collagen gels with embedded axons were stretched and the resulting axon signals were measured, but these experiments were unable to measure the local axon strain fields. Computational discrete fiber network models can directly determine axon strain fields due to tissue scale loading. Therefore, this study used a discrete fiber network model to identify how heterogeneous collagen networks (networks with multiple collagen fiber densities) change axon strain due to tissue scale loading. In this model, a composite cylinder (axon) was embedded in a Delaunay network (collagen). Homogeneous networks with a single collagen volume fraction and two types of heterogeneous networks with either a sparse center or dense center were created. Measurements of fiber forces show higher magnitude forces in sparse regions of heterogeneous networks and uniform force distributions in homogeneous networks. The average axon strain in the sparse center networks decreases when compared to homogeneous networks with similar collagen volume fractions. In dense center networks, the average axon strain increases compared to homogeneous networks. The top 1% of axon strains are unaffected by network heterogeneity. Based on these results, the interaction of tissue scale loading, collagen network heterogeneity, and axon strains in native musculoskeletal tissues should be considered when investigating the source of joint pain.

Increased substance P and synaptic remodeling occur in the trigeminal sensory system with sustained osteoarthritic temporomandibular joint sensitivity.

INTRODUCTION: Temporomandibular joint (TMJ) pain is among the most prevalent musculoskeletal conditions and can result from atypical joint loading. Although TMJ pain is typically self-resolving, 15% of patients develop chronic TMJ pain that is recalcitrant to therapy and may be attributed to changes in pain processing centers. Although TMJ overloading induces pain and osteoarthritis, whether neuronal modifications in the trigeminal sensory system contribute to persistent TMJ pain is unknown. OBJECTIVE: This study investigates changes in excitatory neuropeptides and synaptic transmission proteins in cases of transient and persistent TMJ sensitivity in a rat model. METHODS: Rats underwent repeated jaw loading that produces transient (2N-load) or persistent (3.5N-load) sensitivity. In both groups, immunolabeling was used to assess substance P in the spinal trigeminal nucleus caudalis (Sp5C) and glutamate transporter 1 in the ventroposteriomedial thalamus early after loading. Synaptosomal Western blots were used to measure synaptic proteins in the caudal medulla and thalamus at a later time after loading. RESULTS: Substance P increases transiently in the Sp5C early after loading that induces persistent sensitivity. However, glutamate transporter 1 is unchanged in the ventroposteriomedial thalamus. At a later time, synaptosomal Western blots show loss of the presynaptic tethering protein, synapsin, and the inhibitory scaffolding protein, gephyrin, in the thalamus with persistent, but not transient, sensitivity. No changes are identified in synapsin, phosphorylated synapsin, homer, or gephyrin in the caudal medulla. CONCLUSIONS: Substance P in the Sp5C and later loss of inhibitory synapses in the thalamus likely contribute to, or indicate, persistent TMJ pain.

Early changes in brain network topology and activation of affective pathways predict persistent pain in the rat.

Adaptations in brain communication are associated with multiple pain disorders and are hypothesized to promote the transition from acute to chronic pain. Despite known increases in brain synaptic activity, it is unknown if and how changes in pathways and networks contribute to persistent pain. A tunable rat model that induces transient or persistent temporomandibular joint pain was used to characterize brain network and subcircuit changes when sensitivity is detected in both transient and persistent pain groups and later when sensitivity is present only for the persistent pain group. Brain activity was measured by F-FDG positron emission tomography imaging and used to construct intersubject correlation networks; network connectivity distributions, diagnostics, and community structure were assessed. Activation of subcircuits was tested by structural equation modeling. Findings reveal differences in the brain networks at day 7 between the persistent and transient pain groups, a time when peripheral sensitivity is detected in both groups, but spontaneous pain occurs only in the persistent pain group. At day 7, increased (P ≤ 0.01) clustering, node strength, network segregation, and activation of prefrontal-limbic pathways are observed only in the group that develops persistent pain. Later, increased clustering and node strength are more pronounced with persistent pain, particularly within the limbic system, and decrease when pain resolves. Pretreatment with intra-articular etanercept to attenuate pain confirms that these adaptations are associated with pain onset. Results suggest that early and sustained brain changes can differentiate persistent and transient pain, implying they could be useful as prognostic biomarkers for persistent pain and in identifying therapeutic targets.

Intra-articular collagenase in the spinal facet joint induces pain, DRG neuron dysregulation and increased MMP-1 absent evidence of joint destruction.

Degeneration is a hallmark of painful joint disease and is mediated by many proteases that degrade joint tissues, including collagenases. We hypothesized that purified bacterial collagenase would initiate nociceptive cascades in the joint by degrading the capsular ligament's matrix and activating innervating pain fibers. Intra-articular collagenase in the rat facet joint was investigated for its effects on behavioral sensitivity, joint degeneration, and nociceptive pathways in the peripheral and central nervous systems. In parallel, a co-culture collagen gel model of the ligament was used to evaluate effects of collagenase on microscale changes to the collagen fibers and embedded neurons. Collagenase induced sensitivity within one day, lasting for 3 weeks (p < 0.001) but did not alter ligament structure, cartilage health, or chondrocyte homeostasis. Yet, nociceptive mediators were increased in the periphery (substance P, pERK, and MMP-1; p ≤ 0.039) and spinal cord (substance P and MMP-1; p ≤ 0.041). The collagen loss (p = 0.008) induced by exposing co-cultures to collagenase was accompanied by altered neuronal activity (p = 0.002) and elevated neuronal MMP-1 (p < 0.001), suggesting microscale collagen degradation mediates sensitivity in vivo. The induction of sustained sensitivity and nociception without joint damage may explain the clinical disconnect in which symptomatic joint pain patients present without radiographic evidence of joint destruction.

Synthetic Secoisolariciresinol Diglucoside Attenuates Established Pain, Oxidative Stress and Neuroinflammation in a Rodent Model of Painful Radiculopathy.

Painful cervical radiculopathy is characterized by chronic neuroinflammation that lowers endogenous antioxidant responses leading to the development of oxidative stress and pain after neural trauma. Therefore, antioxidants such as secoisolariciresinol diglucoside (SDG), that promote antioxidant signaling and reduce oxidative damage may also provide pain relief. This study investigated if repeated systemic administration of synthetic SDG after a painful root compression reduces the established pain, oxidative stress and spinal glial activation that are typically evident. SDG was administered on days 1-3 after compression and the extent of oxidative damage in the dorsal root ganglia (DRG) and spinal cord was measured at day 7 using the oxidative stress markers 8-hydroxguanosine (8-OHG) and nitrotyrosine. Spinal microglial and astrocytic activation were also separately evaluated at day 7 after compression. In addition to reducing pain, SDG treatment reduced both spinal 8-OHG and nitrotyrosine, as well as peripheral 8-OHG in the DRG. Moreover, SDG selectively reduced glial activation by decreasing the extent of astrocytic but not microglial activation. These findings suggest that synthetic SDG may attenuate existing radicular pain by suppressing the oxidative stress and astrocytic activation that develop after painful injury, possibly identifying it as a potent therapeutic for painful radiculopathies.

Immediate inhibition of spinal secretory phospholipase A2 prevents the pain and elevated spinal neuronal hyperexcitability and neuroimmune regulatory genes that develop with nerve root compression.

Cervical nerve root injury induces a host of inflammatory mediators in the spinal cord that initiate and maintain neuronal hyperexcitability and pain. Secretory phospholipase A2 (sPLA2) is an enzyme that has been implicated as a mediator of pain onset and maintenance in inflammation and neural injury. Although sPLA2 modulates nociception and excitatory neuronal signaling in vitro, its effects on neuronal activity and central sensitization early after painful nerve root injury are unknown. This study investigated whether inhibiting spinal sPLA2 at the time of nerve root compression (NRC) modulates the pain, dorsal horn hyperexcitability, and spinal genes involved in glutamate signaling, nociception, and inflammation that are seen early after injury. Rats underwent a painful C7 NRC injury with immediate intrathecal administration of the sPLA2 inhibitor thioetheramide-phosphorlycholine. Additional groups underwent either injury alone or sham surgery. One day after injury, behavioral sensitivity, spinal neuronal excitability, and spinal cord gene expression for glutamate receptors (mGluR5 and NR1) and transporters (GLT1 and EAAC1), the neuropeptide substance P, and pro-inflammatory cytokines (TNFα, IL1α, and IL1ß) were assessed. Treatment with the sPLA2 inhibitor prevented mechanical allodynia, attenuated neuronal hyperexcitability in the spinal dorsal horn, restored the proportion of spinal neurons classified as wide dynamic range, and reduced genes for mGluR5, substance P, IL1α, and IL1ß to sham levels. These findings indicate spinal regulation of central sensitization after painful neuropathy and suggest that spinal sPLA2 is implicated in those early spinal mechanisms of neuronal excitability, perhaps via glutamate signaling, neurotransmitters, or inflammatory cascades.

Phospholipase A2 Inhibitor-Loaded Phospholipid Micelles Abolish Neuropathic Pain.

Treating persistent neuropathic pain remains a major clinical challenge. Current conventional treatment approaches carry a substantial risk of toxicity and provide only transient pain relief. In this work, we show that the activity and expression of the inflammatory mediator secretory phospholipase-A2 (sPLA2) enzyme increases in the spinal cord after painful nerve root compression. We then develop phospholipid micelle-based nanoparticles that release their payload in response to sPLA2 activity. Using a rodent model of neuropathic pain, phospholipid micelles loaded with the sPLA2 inhibitor, thioetheramide-PC (TEA-PC), are administered either locally or intravenously at the time of painful injury or 1-2 days afterward. Local micelle administration immediately after compression prevents pain for up to 7 days. Delayed intravenous administration of the micelles attenuates existing pain. These findings suggest that sPLA2 inhibitor-loaded micelles can be a promising anti-inflammatory nanotherapeutic for neuropathic pain treatment.

Changes in Neuronal Activity in the Anterior Cingulate Cortex and Primary Somatosensory Cortex With Nonlinear Burst and Tonic Spinal Cord Stimulation.

INTRODUCTION: Although nonlinear burst and tonic SCS are believed to treat neuropathic pain via distinct pain pathways, the effectiveness of these modalities on brain activity in vivo has not been investigated. This study compared neuronal firing patterns in the brain after nonlinear burst and tonic SCS in a rat model of painful radiculopathy. METHODS: Neuronal activity was recorded in the ACC or S1 before and after nonlinear burst or tonic SCS on day 7 following painful cervical nerve root compression (NRC) or sham surgery. The amplitude of nonlinear burst SCS was set at 60% and 90% motor threshold to investigate the effect of lower amplitude SCS on brain activity. Neuronal activity was recorded during and immediately following light brush and noxious pinch of the paw. Change in neuron firing was measured as the percent change in spikes post-SCS relative to pre-SCS baseline. RESULTS: ACC activity decreases during brush after 60% nonlinear burst compared to tonic (p < 0.05) after NRC and compared to 90% nonlinear burst (p < 0.04) and pre-SCS baseline (p < 0.03) after sham. ACC neuron activity decreases (p < 0.01) during pinch after 60% and 90% nonlinear burst compared to tonic for NRC. The 60% of nonlinear burst decreases (p < 0.02) ACC firing during pinch in both groups compared to baseline. In NRC S1 neurons, tonic SCS decreases (p < 0.01) firing from baseline during light brush; 60% nonlinear burst decreases (p < 0.01) firing from baseline during brush and pinch. CONCLUSIONS: Nonlinear burst SCS reduces firing in the ACC from a painful stimulus; a lower amplitude nonlinear burst appears to have the greatest effect. Tonic and nonlinear burst SCS may have comparable effects in S1.

Intra-articular etanercept attenuates pain and hypoxia from TMJ loading in the rat.

Mechanical overloading of the temporomandibular joint (TMJ) and biochemical changes, like inflammation and hypoxia, contribute to cartilage degeneration and pain associated with osteoarthritis (OA). Yet, how overloading contributes to early dysregulation of chondrocytes is not understood, limiting the development of diagnostics and treatments for TMJ OA. Hypoxia-inducible factors (HIF)-1α/2α in chondrocytes were evaluated at Days 8 and 15 in a rat TMJ pain model induced by jaw loading (1 h/day for 7 days) using immunohistochemistry and compared between cases that induce persistent (3.5 N), acute (2 N), or no (0 N) sensitivity. Hypoxia was measured on Day 8 by immunolabeling of the tracer EF5 and 18 F-EF5 PET imaging. To assess the role of tumor necrosis factor (TNF) in painful TMJ loading, intra-articular etanercept was given before loading. Orofacial sensitivity was evaluated during and after loading. Facial grimace, TNF-α, HIF-2α, and hypoxia levels in the TMJ were measured after loading. HIF-2α was elevated (P = .03) after 3.5 N loading at Day 8, but HIF-1α was unchanged. EF5 uptake increased on Day 8 in the 3.5 N group (P < .048) by tissue assay and 18 F-EF5 PET. At Day 8, both HIF-2α (P = .01) and EF5 uptake (P = .005) were correlated with loading magnitude. Etanercept attenuated sensitivity (P < .01) and the facial grimace on Day 7 (P = .01). It also reduced (P < .01) HIF-2α and EF5 uptake on Day 8; but TNF-α levels were not different from controls at that time. Findings suggest that TMJ loading that induces persistent sensitivity upregulates the catabolic factor HIF-2α and reduces oxygen levels in the cartilage, which may be TNF-driven.

Burst & High-Frequency Spinal Cord Stimulation Differentially Effect Spinal Neuronal Activity After Radiculopathy.

Although burst and high-frequency (HF) spinal cord stimulation (SCS) relieve neuropathic pain, their effects on neuronal hyperexcitability have not been compared. Specifically, it is unknown how the recharge components of burst SCS-either actively balanced or allowed to passively return-and/or different frequencies of HF SCS compare in altering neuronal activity. Neuronal firing rates were measured in the spinal dorsal horn on day 7 after painful cervical nerve root compression in the rat. Motor thresholds (MTs) and evoked neuronal recordings were collected during noxious stimuli before (baseline) and after delivery of SCS using different SCS modes: 10 kHz HF, 1.2 kHz HF, burst with active recharge, or burst with passive recharge. Spontaneous firing rates were also evaluated at baseline and after SCS. The average MT for 10 kHz SCS was significantly higher (p < 0.033) than any other mode. Burst with passive recharge was the only SCS mode to significantly reduce evoked (p = 0.019) and spontaneous (p = 0.0076) firing rates after noxious pinch. This study demonstrates that HF and burst SCS have different MTs and effects on both evoked and spontaneous firing rates, indicating they have different mechanisms of providing pain relief. Since burst with passive recharge was the only waveform to reduce firing, that waveform may be important in the neurophysiological response to stimulation.

Pain After Whole-Body Vibration Exposure Is Frequency Dependent and Independent of the Resonant Frequency: Lessons From an In Vivo Rat Model.

Occupational whole-body vibration (WBV) increases the risk of developing low back and neck pain; yet, there has also been an increased use of therapeutic WBV in recent years. Although the resonant frequency (fr) of the spine decreases as the exposure acceleration increases, effects of varying the vibration profile, including peak-to-peak displacement (sptp), root-mean-squared acceleration (arms), and frequency (f), on pain onset are not known. An established in vivo rat model of WBV was used to characterize the resonance of the spine using sinusoidal sweeps. The relationship between arms and fr was defined and implemented to assess behavioral sensitivity-a proxy for pain. Five groups were subjected to a single 30-min exposure, each with a different vibration profile, and a sham group underwent only anesthesia exposure. The behavioral sensitivity was assessed at baseline and for 7 days following WBV-exposure. Only WBV at 8 Hz induced behavioral sensitivity, and the higher arms exposure at 8 Hz led to a more robust pain response. These results suggest that the development of pain is frequency-dependent, but further research into the mechanisms leading to pain is warranted to fully understand which WBV profiles may be detrimental or beneficial.