Mol Pain
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N-acetylaspartylglutamate (NAAG) is the third most prevalent and widely distributed neurotransmitter in the mammalian nervous system. NAAG activates a group II metabotropic glutamate receptor (mGluR3) and is inactivated by an extracellular enzyme, glutamate carboxypeptidase II (GCPII) in vivo. Inhibitors of this enzyme are analgesic in animal models of inflammatory, neuropathic and bone cancer pain. ⋯ Footpad inflammation increases release of glutamate in the contralateral locus coeruleus and systemic treatment with a GCPII inhibitor blocks this increase. Direct injection of GCPII inhibitors into the contralateral or ipsilateral locus coeruleus reduces both phases of the inflammatory pain response in a dose-dependent manner and the contralateral effect also is blocked by intrathecal injection of an alpha 2 adrenergic receptor antagonist. These data support the hypothesis that the analgesic efficacy of systemically administered GCPII inhibitors is mediated, at least in part, by the contralateral locus coeruleus via group II mGluR, AMPA and alpha 2 adrenergic receptors.
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Caloric restriction is associated with broad therapeutic potential in various diseases and an increase in health and life span. In this study, we assessed the impact of caloric restriction on acute and inflammatory nociception in mice, which were either fed ad libitum or subjected to caloric restriction with 80% of the daily average for two weeks. ⋯ Our data suggest that caloric restriction has an impact on inflammatory nociception which might involve AMP-activated kinase activation and an increased activity of the endogenous endocannabinoid system by caloric restriction-induced cannabinoid receptor type 1 upregulation.
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Platinum-based chemotherapeutic agents, such as cisplatin, are still frequently used for treating various types of cancer. Besides its high effectiveness, cisplatin has several serious side effects. One of the most common side effects is dorsal root ganglion (DRG) neurotoxicity. ⋯ EM and histology showed no evidence of any structural damage, apoptosis or necrosis in DRG cells after cisplatin exposure for 26 days. Furthermore, no nuclear DNA damage in sensory neurons was observed. Here, we provide evidence for a mainly functionally driven induction of neuropathic pain by cisplatin.
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Background Chronic visceral pain is a defining symptom of many gastrointestinal disorders. The KV7 family (KV7.1-KV7.5) of voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pain pathways. Here, we use a combination of immunohistochemistry, gut-nerve electrophysiological recordings in both mouse and human tissues, and single-cell qualitative real-time polymerase chain reaction of gut-projecting sensory neurons, to investigate the contribution of peripheral KV7 channels to visceral nociception. ⋯ In human bowel tissues, KV7.3 and KV7.5 were expressed in neuronal varicosities co-labelled with synaptophysin and CGRP, and retigabine inhibited bradykinin-induced afferent activation in afferent recordings from human colon. Conclusions We show that KV7 channels contribute to the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in both mouse and human gut tissues. As such, peripherally restricted KV7 openers may represent a viable therapeutic modality for the treatment of gastrointestinal pathologies.
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N-methyl-D-aspartate (NMDA) receptor overactivation is involved in neuronal damage after stroke. However, the mechanism underlying NMDA receptor-mediated excitotoxicity remains unclear. In this study, we confirmed that excessive activation of NMDARs led to cell apoptosis in PC12 cells and in primary cultured cortical neurons, which was mediated predominantly by the GluN2B-containing, but not the GluN2A-containing NMDARs. ⋯ Furthermore, we identified that GluN2B-containing NMDARs underwent endocytosis during excessive NMDA treatment. Peptides specifically disrupting the interaction between GluN2B and AP-2 complex not only blocked endocytosis of GluN2B induced by NMDA treatment but also abolished NMDA-induced excitotoxicity. These results demonstrate that Clathrin-dependent endocytosis of GluN2B-containing NMDARs is critical to NMDA-induced excitotoxicity in PC12 cells and in primary cultured cortical neurons, and therefore provide a novel target for blocking NMDAR-mediated excitotoxicity.