Mol Pain
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Background: Accumulating evidence shows that N6-methyladenosine (m6A) modulators contribute to the process of chronic pain. However, the exact mechanisms of m6A writers involved in visceral hypersensitivity of Irritable bowel syndrome (IBS) remain unclear. This article aimed to reveal a new mechanism for the progression of IBS. ⋯ Moreover, YTHDC1, the only m6A-associated protein predicted by bioinformatics to bind to circKcnk9, modulated visceral hypersensitivity through regulating the nuclear export of circKcnk9 in an m6A-dependent manner. Notably, FISH data suggested that the increased nuclear staining of circKcnk9 caused by siYTHDC1 could be recovered by overexpression of YTHDC1 wild type (WT) but not YTHDC1 negative control (NC) in PC12 cells. Conclusions: Our findings reveal a new regulatory mechanism in progress of IBS, that is, METTL3 modulates visceral hypersensitivity through regulating the nuclear export of circKcnk9 in YTHDC1-dependent manner.
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Noncoding microRNAs have emerged as critical players of gene expression in the nervous system, where they contribute to regulating nervous disease. As stated in previous research, the miR-155-5p upregulation happens in the spinal cord at the nociceptive state. It was unclear if miR-155-5p is linked to bone cancer pain (BCP). Herein, we aimed at investigating the miR-155-5p functional regulatory function in BCP process and delineating the underlying mechanism. ⋯ The study findings stated the miR-155-5p pivotal role in regulating BCP by directly targeting TCF4 in spinal neurons and suggested that miR-155-5p could be a promising target in treating BCP.
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T-type Ca2+ channels play a dual role in modulating the excitability of dorsal root ganglia neurons.
A subgroup of low-threshold dorsal root ganglia (DRG) neurons discharge action potentials (APs) with an afterdepolarizing potential (ADP). The ADP is formed by T-type Ca2+ currents. It is known that T-type Ca2+ currents contribute to neuropathic pain. ⋯ After injury, the proportion of DRG neurons with large T-type Ca2+ currents increased in parallel with the increase in the incidence of large-amplitude-ADP firing. And in addition to Cav3.2, Cav3.3 channels are also likely to contribute to low-threshold firing. The data revealed that T-type Ca2+ channels may play a dual role in modulating the injured neurons' high excitability through a cooperative process with Na+ channels, thereby contributing to neuropathic pain.
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DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in neurons in mammals. However, effects of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) expression and hydroxymethylation status on neuron injury remain unclear. This study was designed to explore the effects of TET1 and TET2 expression in the inflammatory pain of rats induced by complete Freund's adjuvant (CFA). ⋯ Intrathecal administration of Bobcat339 improved mechanical and thermal pain threshold in CFA rats. Our findings highlight the role of TET1 in chronic inflammatory pain model. The expression of TET1 was increased in CFA rats, and suppression of TET1 will ameliorate inflammatory pain.
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Randomized Controlled Trial
Human safety study of a selective neuronal adenylate cyclase 1 (AC1) inhibitor NB001 which relieves the neuropathic pain and blocks ACC in adult mice.
Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. ⋯ Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models of neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of long-term potentiation (LTP). These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.