Objective The objective of the current study is to define whether intra-articular nerve growth factor (NGF), an inflammatory mediator that contributes to osteoarthritic pain, is necessary and sufficient for the development or maintenance of injury-induced facet joint pain and its concomitant spinal neuronal hyperexcitability. Method Male Holtzman rats underwent painful cervical facet joint distraction or sham procedures. Mechanical hyperalgesia was assessed in the forepaws, and NGF expression was quantified in the C6/C7 facet joint. An anti-NGF antibody was administered intra-articularly in additional rats immediately or 1 day following facet distraction or sham procedures to block intra-articular NGF and test its contribution to initiation and/or maintenance of facet joint pain and spinal neuronal hyperexcitability. NGF was injected into the bilateral C6/C7 facet joints in separate rats to determine if NGF alone is sufficient to induce these behavioral and neuronal responses. Results NGF expression increases in the cervical facet joint in association with behavioral sensitivity after that joint’s mechanical injury. Intra-articular application of anti-NGF immediately after a joint distraction prevents the development of both injury-induced pain and hyperexcitability of spinal neurons. Yet, intra-articular anti-NGF applied after pain has developed does not attenuate either behavioral or neuronal hyperexcitability. Intra-articular NGF administered to the facet in naïve rats also induces behavioral hypersensitivity and spinal neuronal hyperexcitability. Conclusion Findings demonstrate that NGF in the facet joint contributes to the development of injury-induced joint pain. Localized blocking of NGF signaling in the joint may provide potential treatment for joint pain.

Background Whole-body vibration (WBV) is associated with back and neck pain in military personnel and civilians. However, the role of vibration frequency and the physiological mechanisms involved in pain symptoms are unknown. Questions/purposes This study asked the following questions: (1) What is the resonance frequency of the rat spine for WBV along the spinal axis, and how does frequency of WBV alter the extent of spinal compression/ extension? (2) Does a single WBV exposure at resonance induce pain that is sustained? (3) Does WBV at resonance alter the protein kinase C epsilon (PKCe) response in the dorsal root ganglia (DRG)? (4) Does WBV at resonance alter expression of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn? (5) Does WBV at resonance alter the spinal neuroimmune responses that regulate pain? Methods Resonance of the rat (410 ± 34 g, n = 9) was measured by imposing WBV at frequencies from 3 to 15 Hz. Separate groups (317 ± 20 g, n = 10/treatment) underwent WBV at resonance (8 Hz) or at a nonresonant frequency (15 Hz). Behavioral sensitivity was assessed throughout to measure pain, and PKCe in the DRG was quantified as well as spinal CGRP, glial activation, and cytokine levels at Day 14. Results Accelerometer-based thoracic transmissibility peaks at 8 Hz (1.86 ± 0.19) and 9 Hz (1.95 ± 0.19, mean difference [MD] 0.290 ± 0.266, p \ 0.03), whereas the video-based thoracic transmissibility peaks at 8 Hz (1.90 ± 0.27), 9 Hz (2.07 ± 0.20), and 10 Hz (1.80 ± 0.25, MD 0.359 ± 0.284, p \ 0.01). WBV at 8 Hz produces more cervical extension (0.745 ± 0.582 mm, MD 0.242 ± 0.214, p \ 0.03) and compression (0.870 ± 0.676 mm, MD 0.326 ± 0.261, p \ 0.02) than 15 Hz (extension, 0.503 ± 0.279 mm; compression, 0.544 ± 0.400 mm). Pain is longer lasting (through Day 14) and more robust (p \ 0.01) after WBV at the resonant frequency (8 Hz) compared with 15 Hz WBV. PKCe in the nociceptors of the DRG increases according to the severity of WBV with greatest increases after 8 Hz WBV (p \ 0.03). However, spinal CGRP, cytokines, and glial activation are only evident after painful WBV at resonance. Conclusions WBV at resonance produces long-lasting pain and widespread activation of a host of nociceptive and neuroimmune responses as compared with WBV at a nonresonance condition. Based on this work, future investigations into the temporal and regional neuroimmune response to resonant WBV in both genders would be useful.

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Highly efficient antioxidants based on superoxide dismutase (SOD) -loaded porous polymersomes are developed for treating neuropathic pain. The SOD-loaded porous polymersomes are highly permeable to superoxide radical, while retaining the antioxidant enzyme within their aqueous interiors. Administration of the antioxidant porous polymersomes following a painful nerve root compression is substantially more effective in preventing the onset of pain in rats than comparable or higher doses of free SOD alone.

Structured Abstract Study Design In vivo study defining expression of the neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in cervical intervertebral discs following painful whole body vibration. Objective The goal of this study is to determine if BDNF and NGF are expressed in cervical discs after painful whole body vibration in a rat model. Summary of Background Data Whole body vibration is a possible source of neck pain and has been implicated as increasing the risk for disc disorders. Typically anneural regions of painful human lumbar discs exhibit hyper-innervation, suggesting nerve in-growth as potentially contributing to disc degeneration and pain. BDNF and NGF are upregulated in painfully degenerate lumbar discs and hypothesized to contribute to this pathology. Methods Male Holtzman rats underwent seven days of repeated whole body vibration (15Hz, 30 minutes/day) or sham exposures, followed by seven days of rest. Cervical discs were collected for analysis of BDNF and NGF expression through RT-qPCR and western blot analysis. Immunohistochemistry also evaluated their regional expression in the disc. Results Vibration significantly increases BDNF mRNA levels (p=0.036), as well as total NGF mRNA (p=0.035). Protein expression of both BDNF (p=0.006) and the 75kDa NGF (p=0.045) increase by nearly 4- and 10-fold, respectively. Both BDNF mRNA (R2=0.396 p=0.012) and protein (R2=0.280; p=0.035) levels are significantly correlated with the degree of behavioral sensitivity (i.e. pain) at day 14. Total-NGF mRNA is also significantly correlated with the extent of behavioral sensitivity (p=0.044, R2=0.276). Both neurotrophins are most increased in the inner annulus fibrosus and nucleus pulposus. Conclusion The increases in BDNF and NGF in the cervical discs after painful vibration are observed in typically anneural regions of the disc, consistent with reports of its hyper-innervation. Yet, the induction of nerve in-growth into the disc was not explicitly investigated. Neurotrophin expression also correlates with behavioral sensitivity, suggesting a role for both neurotrophins in the development of disc pain.

Painful neuropathic injuries are accompanied by robust inflammatory and oxidative stress responses that contribute to the development and maintenance of pain. After neural trauma the inflammatory enzyme cyclooxygenase-2 (COX-2) increases concurrent with pain onset. Although pre-treatment with the COX-2 inhibitor, meloxicam, before a painful nerve root compression prevents the development of pain, the pathophysiological mechanisms are unknown. This study evaluated if pre-treatment with meloxicam prior to painful root injury prevents pain by reducing spinal inflammation and peripheral oxidative stress. Glial activation and expression of the inflammatory mediator secreted phospholipase A (sPLA) in the spinal cord were assessed at day 7 using immunohistochemistry. The extent of oxidative damage was measured using the oxidative stress marker, 8-hydroxyguanosine (8-OHG) and localization of 8-OHG with neurons, microglia and astrocytes in the spinal cord and peripherally in the dorsal root ganglion (DRG) at day 7. In addition to reducing pain, meloxicam reduced both spinal microglial and astrocytic activation at day 7 after nerve root compression. Spinal sPLA was also reduced with meloxicam treatment, with decreased production in neurons, microglia and astrocytes. Oxidative damage following nerve root compression was found predominantly in neurons rather than glial cells. The expression of 8-OHG in DRG neurons at day 7 was reduced with meloxicam. These findings suggest that meloxicam may prevent the onset of pain following nerve root compression by suppressing inflammation and oxidative stress both centrally in the spinal cord and peripherally in the DRG.

Whole-body vibration (WBV) is linked epidemiologically to neck and back pain in humans, and to forepaw mechanical allodynia and cervical neuroinflammation in a rodent model of WBV, but the response of the low back and lumbar spine to WBV is unknown. A rat model of WBV was used to determine the effect of different WBV exposures on hind paw behavioral sensitivity and neuroinflammation in the lumbar spinal cord. Rats were exposed to 30 min of WBV at either 8 or 15 Hz on days 0 and 7, with the lumbar spinal cord assayed using immunohistochemistry at day 14. Behavioral sensitivity was measured using mechanical stimulation of the hind paws to determine the onset, persistence, and/or recovery of allodynia. Both WBV exposures induce mechanical allodynia 1 day following WBV, but only the 8 Hz WBV induces a sustained decrease in the withdrawal threshold through day 14. Similarly, increased activation of microglia, macrophages, and astrocytes in the superficial dorsal horn of the lumbar spinal cord is only evident after the painful 8 Hz WBV. Moreover, extracellular signal-regulated kinase (ERK)-phosphorylation is most robust in neurons and astrocytes of the dorsal horn, with the most ERK phosphorylation occurring in the 8 Hz group. These findings indicate that a WBV exposure that induces persistent pain also induces a host of neuroimmune cellular activation responses that are also sustained. This work indicates there is an injury-dependent response that is based on the vibration parameters, providing a potentially useful platform for studying mechanisms of painful spinal injuries. ß

Chronic joint pain is a widespread problem that frequently occurs with aging and trauma. Pain occurs most often in synovial joints, the body's load bearing joints. The mechanical and molecular mechanisms contributing to synovial joint pain are reviewed using two examples, the cervical spinal facet joints and the temporomandibular joint (TMJ). Although much work has focused on the macroscale mechanics of joints in health and disease, the combined influence of tissue mechanics, molecular processes, and nociception in joint pain has only recently become a focus. Trauma and repeated loading can induce structural and biochemical changes in joints, altering their microenvironment and modifying the biomechanics of their constitutive tissues, which themselves are innervated. Peripheral pain sensors can become activated in response to changes in the joint microenvironment and relay pain signals to the spinal cord and brain where pain is processed and perceived. In some cases, pain circuitry is permanently changed, which may be a potential mechanism for sustained joint pain. However, it is most likely that alterations in both the joint microenvironment and the central nervous system (CNS) contribute to chronic pain. As such, the challenge of treating joint pain and degeneration is temporally and spatially complicated. This review summarizes anatomy, physiology, and pathophysiology of these joints and the sensory pain relays. Pain pathways are postulated to be sensitized by many factors, including degeneration and biochemical priming, with effects on thresholds for mechanical injury and/or dysfunction. Initiators of joint pain are discussed in the context of clinical challenges including the diagnosis and treatment of pain.