Mol Pain
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Peripheral somatosensory neurons are frequently exposed to mechanical forces. Strong stimuli result in neuronal activation of high-threshold mechanosensory afferent neurons, even in the absence of tissue damage. Among these neurons, fast-conducting nociceptors (A-fiber high-threshold mechanoreceptors (AHTMRs)) are normally resistant to sustained activation, transiently encoding the mechanical stimulus intensity but not its full duration. ⋯ Moreover, this phenomenon appears to be unique to this subset of afferent neurons and is absent in slow-conducting C-mechanonociceptors (C-fiber high-threshold mechanoreceptors) and rapidly adapting fast-conducting low-threshold mechanoreceptors. Furthermore, this mechanism for rapid adaptation and reducing ongoing input is ablated by repeated strong stimuli and in sensitized AHTMRs after chronic neuropathic injury. Further studies to understand the underling molecular mechanisms behind this phenomenon and their modulation during the development of pathological conditions may provide new targets to control nociceptive hyperexcitability and chronic pain.
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Painful peripheral neuropathy is a severe side effect in oxaliplatin therapy that compromises cancer patients' quality of life. However, its underlying pathogenic mechanisms remain largely unknown. Here, we found that intraperitoneal consecutive administration of oxaliplatin significantly increased excitability of small diameter dorsal root ganglion neurons and induced thermal hyperalgesia in rats. ⋯ Importantly, the upregulated CX3CL1 is mediated by the NF-κB signaling pathway, as inhibition of NF-κB p65 activation with pyrrolidine dithiocarbamate or p65 siRNA inhibited the upregulation of CX3CL1, the enhanced excitability of dorsal root ganglion neurons, and thermal hyperalgesia induced by oxaliplatin. Further studies with chromatin immunoprecipitation found that oxaliplatin treatment increased the recruitment of NF-κB p65 to the CX3Cl1 promoter region. Our results suggest that upregulation of CX3CL1 in dorsal root ganglion mediated by NF-κB activation contributes to the peripheral sensitization and chronic pain induced by oxaliplatin administration.
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Previous studies disclosed the pivotal role of methyltransferase complex G9a/Glp in the pathogenesis of neuropathic hypersensitivity induced by peripheral nerve injury. We observed that higher dose of G9a inhibitor improved nociceptive behavior, but the lower dose worsened pain. The aim of this study is to extensively observe the differential effect of various dosages of G9a/Glp inhibitors on nerve injury-induced allodynia. ⋯ Methyltransferase complex G9a/Glp has a threshold role in mediating peripheral nerve injury-induced hypersensitivity at its low level versus high level through inhibiting and facilitating the nociceptive behavior, respectively.
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Blood–nerve barrier disruption is pivotal in the development of neuroinflammation, peripheral sensitization, and neuropathic pain after peripheral nerve injury. Activation of toll-like receptor 4 and inactivation of Sonic Hedgehog signaling pathways within the endoneurial endothelial cells are key events, resulting in the infiltration of harmful molecules and immunocytes within the nerve parenchyma. However, we showed in a previous study that preemptive inactivation of toll-like receptor 4 signaling or sustained activation of Sonic Hedgehog signaling did not prevent the local alterations observed following peripheral nerve injury, suggesting the implication of another signaling pathway. ⋯ A crosstalk between Wnt/β-catenin- and Sonic Hedgehog-mediated signaling pathways within endoneurial endothelial cells could mediate the chronic disruption of the blood–nerve barrier following IoN-CCI, resulting in increased irreversible endoneurial vascular permeability and neuropathic pain development.
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Background Periodontitis is an inflammatory disease accompanied by alveolar bone loss and progressive inflammation without pain. However, the potential contributors eliminating pain associated with gingival inflammation are unknown. Results we examined the involvement of CXC chemokine receptor type 4 (CXCR4) on the mechanical sensitivity of inflamed periodontal tissue, using a mouse model of periodontitis established by the ligation of the tooth cervix of a maxillary second molar and inoculation with Porphyromonas gingivalis (P. gingivalis). ⋯ Moreover, the decrease in MHWT after treatment with P. gingivalis and CXCR4 neutralization was partially reversed by nitric oxide synthase inhibition in the gingival tissue. Nuclear factor-kappa B was expressed in infiltrating macrophages after inoculation of P. gingivalis and administration of the nuclear factor-kappa B activator betulinic acid induced gingival mechanical allodynia in naive mice. Conclusions These findings suggest that CXCR4 signaling inhibits nitric oxide release from infiltrating macrophages and is involved in modulation of the mechanical sensitivity in the periodontal tissue in P. gingivalis-induced periodontitis.