Articles: neuralgia.
-
Besides physical insult, spinal cord injury (SCI) can also result from transient ischemia, such as ischemia-reperfusion SCI (I/R SCI) as a postoperative complication. Increasing evidence has suggested that oxidative stress and related reactive aldehyde species are key contributors to cellular injury after SCI. Previous work in spinal cord contusion injury has demonstrated that acrolein, both a key product and an instigator of oxidative stress, contributes to post-traumatic hyperalgesia. ⋯ Taken together, these results support the causal role of acrolein in inducing hyperalgesia after I/R SCI via activation and upregulation of TRPA1 channels. Furthermore, endogenously produced acrolein resulting from metabolic abnormality in the absence of mechanical insults appears to be capable of heightening pain sensitivity after SCI. Our data also further supports the notion of acrolein scavenging as an effective analgesic as well neuroprotective strategy in conditions where oxidative stress and aldehyde toxicity is implicated.
-
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.
-
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.
-
Clinical evidence indicates that cognitive impairment is a common comorbid condition of chronic pain. However, the cellular basis for chronic pain-mediated cognitive impairment remains unclear. We report here that rats exhibited memory deficits after spared nerve injury (SNI). ⋯ Intracerebroventricular infusion of nocodazole, an MT destabilizer, ameliorated memory deficits in rats with SNI-induced nociceptive behavior. Expression of HDAC6, an α-tubulin deacetylase, was reduced in the hippocampus in rats with cognitive impairment. These findings indicate that peripheral nerve injury (eg, SNI) affects the MT dynamic equilibrium, which is critical to neuronal structure and synaptic plasticity.
-
One specific behavior can be synergistically modulated by different neural pathways. Medial septal (MS) cholinergic system innervates widespread cortical and subcortical regions and participates in pain modulation, but the underlying neural pathways are not fully understood. This study examined the contribution of MS cholinergic neurons and 2 neural pathways: MS-rostral anterior cingulate cortex (rACC) and MS-ventral hippocampal CA1 (vCA1), in modulating perceptual and affective pain behaviors in a mouse model of chronic inflammatory pain. ⋯ By contrast, chemogenetic activation of MS cholinergic neurons also produced analgesia, but by rescuing hypofunctional pyramidal neurons in vCA1. These results clearly demonstrate that the MS cholinergic system differentially modulates chronic inflammatory pain through MS-rACC or MS-vCA1 pathways. More significantly, our research provides evidence for a novel paradigm of neural circuit modulation: MS cholinergic inhibition and activation induce similar analgesia but through distinct neural pathways.