Articles: neuropathic-pain.
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Neurochemical research · May 2018
Picroside II Attenuates CCI-Induced Neuropathic Pain in Rats by Inhibiting Spinal Reactive Astrocyte-Mediated Neuroinflammation Through the NF-κB Pathway.
Reactive astrocyte-mediated neuroinflammatory responses in the spinal dorsal horn have been reported to play a pivotal role in pathological pain. Chronic constriction injury (CCI) enhances the activation of nuclear factor kappa B (NF-κB), which is involved in neuropathic pain (NP). Picroside II (PII), a major active component of Picrorhiza scrophulariiflora, has been investigated for its anti-oxidative, anti-inflammatory, and anti-apoptotic activities. ⋯ Intraperitoneal administration of PII remarkably reversed the CCI-induced mechanical allodynia and thermal hyperalgesia and reduced the mRNA and protein levels of IL-1β, IL-6, and TNF-α in the spinal cord. Additionally, according to the in vitro data, the PII treatment inhibited LPS-induced increases in the mRNA and protein levels of IL-1β, IL-6, and TNF-α and suppressed the NF-κB pathway by inhibiting the phosphorylation of NF-κB/p65 and the degradation of inhibitor of NF-κB (IκB) in astrocytes without toxicity to astrocytes. Overall, the analgesic effect of PII correlated with the inhibition of spinal reactive astrocyte-mediated neuroinflammation through the NF-κB pathway in rats with NP.
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The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen leads to ER stress, which is related to cellular reactive oxygen species production. Neuropathic pain may result from spinal dorsal horn (SDH) ER stress. In this study, we examined the cause-effect relationship between ER stress and neuropathic pain using the spinal nerve ligation (SNL) rat model. ⋯ Other important findings in this study including the following: (1) nociceptive behavior was alleviated in SNL rat as long as tauroursodeoxycholic acid injections were repeated to inhibit ER stress; (2) inducing SDH ER stress in healthy rat resulted in mechanical hyperalgesia; (3) blocking protein disulfide isomerase pharmacologically reduced ER stress and nociceptive behavior in SNL rat; (4) cells in the dorsal horn with elevated ER stress were mainly neurons; and (5) whole-cell recordings made in slide preparations revealed significant inhibition of GABA-ergic interneuron activity in the dorsal horn with ER stress vs in the healthy dorsal horn. Taken together, results of the current study demonstrate that coregulation of ER stress and oxidative stress played an important role in neuropathic pain process. Inhibiting SDH ER stress could be a potential novel strategy to manage neuropathic pain.
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Elevated N-methyl-D-aspartate receptor (NMDAR) activity is linked to central sensitization and chronic pain. However, NMDAR antagonists display limited therapeutic potential because of their adverse side effects. Novel approaches targeting the NR2B-PSD95-nNOS complex to disrupt signaling pathways downstream of NMDARs show efficacy in preclinical pain models. ⋯ Finally, TAT-GESV (i.t.) did not induce NMDAR-mediated motor ataxia in the rotarod test and did not alter basal nociceptive thresholds in the radiant heat tail-flick test. These observations support the hypothesis that antiallodynic efficacy of an nNOS-NOS1AP disruptor may result, at least in part, from blockade of p38 MAPK-mediated downstream effects. Our studies demonstrate, for the first time, that disrupting nNOS-NOS1AP protein-protein interactions attenuates mechanistically distinct forms of neuropathic pain without unwanted motor ataxic effects of NMDAR antagonists.
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Neuropathic pain is thought to be mediated by aberrant impulses from sensitized primary afferents, and the temporal summation of the discharges might also influence nociceptive processing. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Ih current) generate rhythmic activity in neurons within the central nervous system and contribute to nociceptors excitability in neuropathic pain. ⋯ We show an involvement of HCN channels in the modulation of ectopic spontaneous discharges from C-nociceptors. This finding exposes a mechanism of nociceptive transmission enhancement and highlights the clinical relevance of peripheral HCN blockade for spontaneous pain relief during neuropathy.