Articles: hyperalgesia.
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Mitochondria are present at high concentration at the site of sensory transduction in the peripheral terminals of nociceptors. Because nerve growth factor (NGF), which induces nociceptor sensitization by acting on the high-affinity tropomyosin receptor kinase A (TrkA) receptor, also produces local recruitment of mitochondria in DRG neurons, we evaluated the role of mitochondria in NGF-induced mechanical hyperalgesia. ⋯ Disruption of microtubules, which are required for the trafficking and subcellular localization of mitochondria, also attenuated NGF-induced hyperalgesia. Our results suggest a contribution of mitochondrial localization and function to NGF-dependent pain syndromes.
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The aim of this study was to test the hypothesis that nuclear factor-kappa B (NF-κB) is involved in TRPV4-NO pathway in thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rat. Intrathecal administration of two NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC; 10(-1) to 10(-2)M) and BAY (100-50 μM), both induced significantly dose-dependent increase in the paw withdrawal latency (PWL) and decrease in nitric oxide (NO) content in DRG when compared with control rats. ⋯ In addition, Western blot analysis indicated that CCD rats exhibited nuclear NF-κB protein expression and low levels of cytoplasmic inhibitory-kappa B (I-κB) expression; the increase in NF-κB expression and decrease in I-κB expression were reversed after intrathecal injection of PDTC. In conclusion, our data suggested that NF-κB could be involved in TRPV4-NO pathway in CCD-induced thermal hyperalgesia.
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Experimental animal pain models involving peripheral nerve lesions have expanded the understanding of the pathological changes caused by nerve damage. However models for the pathogenesis of chronic pain patients lacking obvious nerve injuries have not been developed to the same extent. Guided by clinical observations, we focused on the initiating noxious event, the context when applying nociceptive stimulation targeting long-lasting pain elicited by muscle insult. ⋯ However, increasing the dose of LPS (20 μg/kg) before applying HS5 eliminated the development of mechanical hypersensitivity in the chronic phase, while the hypersensitivity in the acute phase was significantly more severe than with low-dose LPS-pretreatment. In this model, the development of hypersensitivity could be modulated by manipulating LPS-doses prior to noxious stimulation. This novel chronic pain model based on a preceding 'priming' myalgic stimulus provides an intriguing means for studying the pathogenesis of chronic pain.
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BACKGROUND AND PURPOSE We recently demonstrated that activation of the spinal sigma-1 receptor induces mechanical and thermal hypersensitivity via calcium-dependent second messenger cascades and phosphorylation of the spinal NMDA receptor GluN1 subunit (pGluN1). Here we examined the role of NO in this process, as it plays a critical role in PKC-mediated calcium signalling and the potentiation of NMDA receptor function. EXPERIMENTAL APPROACH The effects of intrathecal (i.t.) pretreatment with nNOS inhibitors on PRE084 (sigma-1 receptor agonist)-induced pain were assessed in mice by use of mechanical allodynia and thermal hyperalgesia tests. ⋯ PRE084 also time-dependently decreased the ratio of phosphorylated nNOS (pnNOS) to nNOS expression and the number of spinal pnNOS-ir cells. This decrease in pnNOS was prevented by BD1047, a sigma-1 receptor antagonist and cyclosporin A, a calcineurin inhibitor, but not by a sGC inhibitor. CONCLUSIONS AND IMPLICATIONS Spinal sigma-1 receptor-induced sensitization is mediated by an increase in nNOS activity, which is associated with an NO-induced increase in PKC-dependent pGluN1 expression.
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J. Neurosci. Methods · Jul 2011
Direct injection into the dorsal root ganglion: technical, behavioral, and histological observations.
Direct injection of agents into the dorsal root ganglia (DRGs) offers the opportunity to manipulate sensory neuron function at a segmental level to explore pathophysiology of painful conditions. However, there is no described method that has been validated in detail for such injections in adult rats. We have found that 2 μl of dye injected through a pulled glass pipette directly into the distal DRG, exposed by a minimal foraminotomy, produces complete filling of the DRG with limited extension into the spinal roots. ⋯ Injection of adeno-associated virus (AAV) vector conveying green fluorescent protein (GFP) transgene resulted in expression as soon as 1 day after injection into the DRG, including fibers in the spinal dorsal horn and columns. AAV injection into the DRG produced additional thermal hypersensitivity and withdrawal from the stroke of a brush and compromised motor performance. These findings demonstrate a method for selective injection of agents into single DRGs for anatomically restricted actions.