Experimental neurology
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Experimental neurology · Oct 2017
Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib.
Bortezomib is a first-line chemotherapeutic drug widely used for multiple myeloma and other nonsolid malignancies. Although bortezomib-induced persistent pain is easily diagnosed in clinic, the pathogenic mechanism remains unclear. Here, we studied this issue with use of a rat model of systemic intraperitoneal administration of bortezomib for consecutive 5days. ⋯ In addition, inhibition of STAT3 activity by S3I-201 attenuated bortezomib-induced mechanical allodynia and central sensitization. Local knockdown of STAT3 also ameliorated the mechanical allodynia induced by bortezomib administration. Our results suggest that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment.
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Experimental neurology · Sep 2017
The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α represents a new antinociceptive signaling pathway in mice.
Recently, α7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti-inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago-allosteric ligands (ago-PAMs), and α7-silent agonists. Activation of α7 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator-activated receptors type-α (PPAR-α), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca2+-dependent manner. ⋯ Conversely, exogenous administration of the naturally occurring PPAR-α agonist PEA potentiated the antinociceptive effects of PNU282987. In contrast, the cannabinoid CB1 antagonist rimonabant and the CB2 antagonist SR144528 failed to reverse the antinociceptive effects of PNU282987. These findings suggest that PPAR-α plays a key role in a putative antinociceptive α7 nicotinic signaling pathway.
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Experimental neurology · Sep 2017
ReviewDeveloping a data sharing community for spinal cord injury research.
The rapid growth in data sharing presents new opportunities across the spectrum of biomedical research. Global efforts are underway to develop practical guidance for implementation of data sharing and open data resources. These include the recent recommendation of 'FAIR Data Principles', which assert that if data is to have broad scientific value, then digital representations of that data should be Findable, Accessible, Interoperable and Reusable (FAIR). ⋯ The goals were to examine the current landscape for data sharing in SCI research and provide a path to its future. Below are highlights from the workshop, including perspectives on the value of data sharing in SCI research, workshop participant perspectives and concerns, descriptions of existing resources and actionable directions for further engaging the SCI research community in a model that may be applicable to many other areas of neuroscience. This manuscript is intended to share these initial findings with the broader research community, and to provide talking points for continued feedback from the SCI field, as it continues to move forward in the age of data sharing.
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Experimental neurology · Sep 2017
Exploring acute-to-chronic neuropathic pain in rats after contusion spinal cord injury.
Spinal cord injury (SCI) causes chronic pain in 65% of individuals. Unfortunately, current pain management is inadequate for many SCI patients. Rodent models could help identify how SCI pain develops, explore new treatment strategies, and reveal whether acute post-SCI morphine worsens chronic pain. ⋯ Our data show that specific rat contusion SCI models cause neuropathic pain. Further, chronic neuropathic pain elicited by these contusion SCIs was not amplified by our course of early post-trauma morphine. Using clinically relevant rat models of SCI could help identify novel pain management strategies.
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Experimental neurology · Sep 2017
The effectiveness of the anti-CD11d treatment is reduced in rat models of spinal cord injury that produce significant levels of intraspinal hemorrhage.
We have previously reported that administration of a CD11d monoclonal antibody (mAb) improves recovery in a clip-compression model of SCI. In this model the CD11d mAb reduces the infiltration of activated leukocytes into the injured spinal cord (as indicated by reduced intraspinal MPO). However not all anti-inflammatory strategies have reported beneficial results, suggesting that success of the CD11d mAb treatment may depend on the type or severity of the injury. ⋯ Lesion analyses revealed increased levels of hemorrhage after contusion SCI compared to clip-compression SCI. SCI that is accompanied by increased intraspinal hemorrhage would be predicted to be refractory to the CD11d mAb therapy as this approach targets leukocyte diapedesis through the intact vasculature. These results suggest that the disparate results of the anti-CD11d treatment in contusion and clip-compression models of SCI are due to the different pathophysiological mechanisms that dominate these two types of spinal cord injuries.