Role of TNF-alpha during central sensitization in preclinical studies

Tumor necrosis factor-alpha (TNF-α) is a principal mediator in pro-inflammatory processes that involve necrosis, apoptosis and proliferation. Experimental and clinical evidence demonstrate that peripheral nerve injury results in activation and morphological changes of microglial cells in the spinal cord. These adjustments occur in order to initiate an inflammatory cascade in response to the damage. Between the agents involved in this reaction, TNF-α is recognized as a key player in this process as it not only modulates lesion formation, but also because it is suggested to induce nociceptive signals. Nowadays, even though the function of TNF-α in inflammation and pain production seems to be generally accepted, diverse sources of literature point to different pathways and outcomes. In this review, we systematically searched and reviewed original articles from the past 10 years on animal models of peripheral nervous injury describing TNF-α expression in neural tissue and pain behavior

Systemic inflammation decreases pain threshold in humans in vivo

Contains fulltext : 126271.pdf (publisher's version ) (Open Access)BACKGROUND: Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods. METHODS AND RESULTS: Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-alpha, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20+/-4 % and 13+/-3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7+/-3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques. CONCLUSIONS AND SIGNIFICANCE: In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception

Tensile stretching of cervical facet joint capsule and related axonal changes

This study examines axonal changes in goat cervical facet joint capsules (FJC) subjected to low rate loading. Left C5–C6 FJC was subjected to a series of tensile tests from 2 mm to failure using a computer-controlled actuator. The FJC strain on the dorsal aspect was monitored by a stereo-imaging system. Stretched (n = 10) and unstretched (n = 7) capsules were harvested and serial sections were processed by a silver impregnation method. The mean peak actuator displacement was 21.3 mm (range: 12–30 mm). The average peak strain encompassing various regions of the capsule was 72.9 ± 7.1%. Complete failure of the capsule was observed in 70% of the stretched capsules. Silver impregnation of the sections revealed nerve fibers and bundles in all the regions of the capsule. A blinded analysis of digital photomicrographs of axons revealed a statistically significant number of swollen axons with non-uniform caliber in stretched FJCs. Axons with terminal retraction balls, with occasional beaded appearance or with vacuolations were also observed. Stretching the FJC beyond physiological range could result in altered axonal morphology that may be related to secondary or delayed axotomy changes similar to those seen in central nervous system injuries where axons are subjected to stretching and shearing. These may contribute to neuropathic pain and are potentially related to neck pain after whiplash events