Article

Up-regulation of TNFα in DRG satellite cells following lumbar facet joint injury in rats

Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, 260-8670 Chiba, Japan.
European Spine Journal (Impact Factor: 2.47). 07/2006; 15(6):953-8. DOI: 10.1007/s00586-005-1031-2
Source: PubMed

ABSTRACT The rat L5/6 facet joint, from which low back pain can originate, is multisegmentally innervated from the L1 to L5 dorsal root ganglia (DRG). Sensory fibers from the L1 and L2 DRG are reported to non-segmentally innervate the paravertebral sympathetic trunks, while those from the L3 to L5 DRGs segmentally innervate the L5/6 facet joint. Tumor necrosis factor alpha (TNFalpha) is a mediator of peripheral and central nervous system inflammatory response and plays a crucial role in injury and its pathophysiology. In the current study, change in TNFalpha in sensory DRG neurons innervating the L5/6 facet joint following facet joint injury was investigated in rats using a retrograde neurotransport method and immunohistochemistry. Neurons innervating the L5/6 facet joints, retrogradely labeled with fluoro-gold (FG), were distributed throughout DRGs from L1 to L5. Most DRG FG-labeled neurons innervating L5/6 facet joints were immunoreactive (IR) for TNFalpha before and after injury. In the DRG, glial fibrillary acidic protein (GFAP)-IR satellite cells emerged and surrounded neurons innervating L5/6 facet joints after injury. These satellite cells were also immunoreactive for TNFalpha. The numbers of activated satellite cells and TNFalpha-IR satellite cells were significantly higher in L1 and L2 DRG than in L3, L4, and L5 DRG. These data suggest that up-regulation of glial TNFalpha may be involved in the pathogenesis of facet joint pain.

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    • "The human clinical studies cited above have major limitations with respect to investigating the underlying mechanisms of low back pain. While numerous animal models exist to investigate major spinal disorders [40] [41] [42] [43] [44] [45], few animal models of lumbar facet joint injury exist [46] [47] [48] [49] [50] [51]. "
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    ABSTRACT: Objective. To develop a novel animal model of persisting lumbar facet joint pain. Methods. Sprague Dawley rats were anaesthetized and the right lumbar (L5/L6) facet joint was exposed and compressed to ~1 mm with modified clamps applied for three minutes; sham-operated and naïve animals were used as control groups. After five days, animals were tested for hind-paw sensitivity using von Frey filaments and axial deep tissue sensitivity by algometer on assigned days up to 28 days. Animals were sacrificed at selected times for histological and biochemical analysis. Results. Histological sections revealed site-specific loss of cartilage in model animals only. Tactile hypersensitivity was observed for the ipsi- and contralateral paws lasting 28 days. The threshold at which deep tissue pressure just elicited vocalization was obtained at three lumbar levels; sensitivity at L1 > L3/4 > L6. Biochemical analyses revealed increases in proinflammatory cytokines, especially TNF-α, IL-1α, and IL-1β. Conclusions. These data suggest that compression of a facet joint induces a novel model of local cartilage loss accompanied by increased sensitivity to mechanical stimuli and by increases in inflammatory mediators. This new model may be useful for studies on mechanisms and treatment of lumbar facet joint pain and osteoarthritis.
    06/2012; 2012:127636. DOI:10.1155/2012/127636
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    • "Previous studies suggested that chemokine signaling has emerged as a key candidate to mediate glia–neuron interaction. SGCs upregulated the production of proinflammatory cytokines such as TNF-α after peripheral nerve injury (Miyagi et al., 2006). "
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    ABSTRACT: The role of satellite glial cells (SGCs) of sensory ganglia in chronic pain begins to receive interest. The present study aims to investigate the contribution of SGC activation to the development of neuropathic pain. A neuropathic pain model was established by lumbar 5 spinal nerve ligation (SNL), and glial fibrillary acidic protein (GFAP) was used as a marker of SGC activation. It was found that SGCs were activated in the ipsilateral dorsal root ganglia (DRG) increased significantly as early as 4h following SNL, gradually increased to a peak level at day 7, and then stayed at a high level to the end of the experiment at day 56. SGC activation in the SNL group was significantly higher than that in the sham group at days 1, 3 and 7 after operation. Immunofluorescent double labeling showed that the activated SGCs encircled large, medium-sized and small neurons. The SGCs surrounded the small and medium-sized neurons were preferentially activated in the early phase, but shifted to large diameter neurons as time went on. Continuous infusion of fluorocitrate, a glial metabolism inhibitor, to the affected DRG via mini-osmotic pump for 7d significantly alleviated mechanical allodynia at day 7. These results suggest that SGCs in the DRG were activated after SNL. SGC activation contributed to the early maintenance of neuropathic pain.
    Brain research 10/2011; 1427:65-77. DOI:10.1016/j.brainres.2011.10.016 · 2.83 Impact Factor
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    • "Inflammatory processes contribute to persistent pain through a variety of mediators (Kawakami and Weinstein, 1986; McMahon et al., 2005; Millan, 1999). Several different animal models of painful joint inflammation have reported cytokine upregulation and glial activation in the dorsal root ganglion (DRG) and spinal cord (Fenzi et al., 2001; Lee et al., 2008; Miyagi et al., 2006). Glial activation can alter neuronal signaling and can also cause excessive glutamate release (Kawakami and Weinstein, 1986). "
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    ABSTRACT: Chronic neck pain is one of the most common musculoskeletal disorders in the US. Although biomechanical and clinical studies have implicated the facet joint as a primary source of neck pain, specific cellular mechanisms still remain speculative. The purpose of this study was to investigate whether a mediator (activating transcription factor; 4ATF4) of the integrated stress response (ISR) is involved in facet-mediated pain. Holtzman rats underwent C6/C7 facet joint loading that produces either painful (n=16) or nonpainful (n=8) responses. A sham group (n=9) was also included as surgical controls. Behavioral sensitivity was measured and the C6 dorsal root ganglia (DRGs) were harvested on day 7 to evaluate the total and neuronal ATF4 expression. In separate groups, an intra-articular ketorolac injection was administered either immediately (D0 ketorolac) or 1 day (D1 ketorolac) after painful facet joint loading. Allodynia was measured at days 1 and 7 after injury to assess the effects on behavioral responses. ATF4 and BiP (an indicator of ISR activation) were separately quantified at day 7. Facet joint loading sufficient to elicit behavioral hypersensitivity produced a threefold increase in total and neuronal ATF4 expression in the DRG. After ketorolac treatment at the time of injury, ATF4 expression was significantly (P<0.01) reduced despite not producing any attenuation of behavioral responses. Interestingly, ketorolac treatment at day 1 significantly (P<0.001) alleviated behavioral sensitivity at day 7, but did not modify ATF4 expression. BiP expression was unchanged after either intervention time. Results suggest that ATF4-dependent activation of the ISR does not directly contribute to persistent pain, but it may sensitize neurons responsible for pain initiation. These behavioral and immunohistochemical findings imply that facet-mediated pain may be sustained through other pathways of the ISR.
    Neuroscience 07/2011; 193:377-86. DOI:10.1016/j.neuroscience.2011.07.059 · 3.33 Impact Factor
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