Articles: neuropathic-pain.
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Journal of neurotrauma · Aug 2018
The Role of Ventral Tegmental Area Gamma-Aminobutyric Acid in Chronic Neuropathic Pain after Spinal Cord Injury in Rats.
Spinal cord injury (SCI) frequently results in chronic neuropathic pain (CNP). However, the understanding of brain neural circuits in CNP modulation is unclear. The present study examined the changes of ventral tegmental area (VTA) putative GABAergic and dopaminergic neuronal activity with CNP attenuation in rats. ⋯ With regard to in vivo electrophysiology, VTA putative GABAergic neuronal activity (13.6 ± 1.7 spikes/sec) and putative dopaminergic neuronal activity (2.4 ± 0.8 spikes/sec) were increased and decreased, respectively, in the SCI group compared to the sham control group. These neuronal activities were reversed by i.v. administration of morphine. The present study suggests that chronic increase of GABAergic neuronal activity suppresses dopaminergic neuronal activity in the VTA and is responsible for negative emotion and motivation for attenuation of SCI-induced CNP.
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Endothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. ⋯ At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1-ETAR-NFAT5 is a novel regulatory mechanism underlying neuropathic pain.
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Brain Behav. Immun. · Aug 2018
Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice.
p38 mitogen-activated protein kinase (MAPK) consists of two major isoforms: p38α and p38β; however, it remains unclear which isoform is more important for chronic pain development. Recently, we developed potent, long-lasting, and p38 MAPK subtype-specific antisense oligonucleotides (ASOs). We examined the therapeutic effects of isoform-specific ASOs in several chronic pain models following single intrathecal injection (300 μg/10 μl) in CD1 mice. ⋯ Intrathecal p38α MAPK ASO pre-treatment also prevented TLR4-mediated mechanical allodynia and downregulated levels of p38α MAPK and phosphorylated p38 MAPK following intrathecal treatment of lipopolysaccharide. In summary, our findings suggest that p38α MAPK is the major p38 MAPK isoform in the spinal cord and regulates chronic pain in a sex and model-dependent manner. Intrathecal p38α MAPK ASO may offer a new treatment for some chronic pain conditions.
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Glial cells play important roles in the development and maintenance of neuropathic pain. In particular, activated microglia in the spinal cord facilitate the hyper-excitability of dorsal horn neurons after peripheral nerve injury via pro-inflammatory molecules. In this study, we investigated the possible involvement of the anti-inflammatory cytokine, interleukin-4 (IL-4), in neuropathic pain. ⋯ Intrathecal administration of recombinant IL-4 suppressed mechanical hypersensitivity in neuropathic rats, and the analgesic effect of IL-4 was accompanied by further enhancement of pSTAT6 expression in spinal microglia. Taken together, these results suggest that the adaptive responses of microglia to nerve injury involve both inflammatory and anti-inflammatory signaling, including IL-4R alpha and pSTAT6. These findings support that utilizing the endogenous anti-nociceptive activity of IL-4R alpha may modify the cell lineage of pro-nociceptive microglia, thus providing a novel therapeutic strategy for neuropathic pain.
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Neurodegeneration is associated with changes in basal cellular function due to the dysregulation of autophagy. A recent study introduced the involvement of autophagy during spinal nerve ligation (SNL). Nefopam has shown potential for reducing neuropathic pain, but the underlying mechanisms are unknown. Here, we investigated the effects of nefopam on neuropathic pain development following SNL, focusing on the involvement of autophagy. ⋯ Collectively, the mode of action of nefopam on neuropathic pain appears to be associated with downregulation of phospho-JNK and autophagy, as well as modulation of the immune response.