LncRNA-UC.25 + shRNA Alleviates P2Y14 Receptor–Mediated Diabetic Neuropathic Pain via STAT1

Wu, Baoguo; Zhou, Chi; Xiao, Zehao; Tang, Gan; Guo, Hongmin; Hu, Zihui; Hu, Qixing; Peng, Hao; Pi, Lingzhi; Zhang, Zhihua; Wang, Miaomiao; Peng, Taotao; Huang, Jiaqi; Liang, Shangdong; Li, Guilin

doi:10.1007/s12035-022-02925-0

Cited by 8 publications

(5 citation statements)

References 25 publications

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“…The relationship between STAT1 and pain has been intensively investigated in previous studies ( Busch-Dienstfertig et al, 2012 ; Song et al, 2017 ; Wu et al, 2022 ). However, it is still unclear whether STAT2 also plays a role in neuropathic pain.…”

Section: Resultsmentioning

confidence: 99%

“…STAT1 plays a key role in chemokine production mediated by tumor necrosis factor-α and/or interferon-γ ( Han et al, 2011 ; Jeong et al, 2015 ). In addition, numerous studies have revealed that STAT1 is involved in neuropathic pain via multiple pathways, including controlling NF-κB p65 nuclear translocation, increasing MHC II expression in microglia, and positively regulating P2Y14 receptors ( Song et al, 2017 ; Guo et al, 2021 ; Wu et al, 2022 ). Recent reports indicate that STAT2, a widespread cytokine regulator, plays a role in inhibiting STAT1 in multiple signaling pathways ( Ho et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Huang

Ding

et al. 2023

Front. Pharmacol.

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Regulation of gene transcription in the spinal dorsal horn (SDH) plays a critical role in the pathophysiology of neuropathic pain. In this study, we investigated whether the transcription factor STAT2 affects neuropathic pain and evaluated its possible mechanisms. A proteomic analysis showed that the nuclear fraction of STAT2 protein in the SDH was downregulated after chronic constriction injury of the rat sciatic nerve, which was associated with the development of neuropathic pain. Similarly, siRNA-induced downregulation of STAT2 in the SDH of naïve rats also resulted in pain hypersensitivity. Using RNA-sequencing analysis, we showed that reduction of nuclear STAT2 after chronic constriction injury was associated with increased expression of microglial activation markers, including the class II transactivator and major histocompatibility complex class II proteins. In addition, siRNA-induced downregulation of STAT2 promoted microglial activation and pro-inflammatory cytokine expression in the SDH. Taken together, these results showed that chronic constriction injury caused downregulation of nuclear STAT2 in the SDH, which may result in microglial activation and development of neuropathic pain. Our findings indicate that restoration of nuclear expression of STAT2 could be a potential pathway for the treatment of neuropathic pain.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Huang

Ding

et al. 2023

Front. Pharmacol.

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“…Numerous studies have shown that P2RY 14 , in the periphery nerves and spinal cord, is a mediator of nociceptive sensitization and in ammation [22,23]. However, the role of P2RY 14 in the brain in pain modulation and EA-induced analgesia remains incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

Electroacupuncture may alleviate inflammatory pain by inhibiting the expression of P2RY14 in the primary somatosensory cortex

Hou,

Zhou,

et al. 2024

Preprint

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Electroacupuncture (EA) has been successfully used to treat painful conditions. However, its analgesic mechanism remains poorly understood. Here, we established a Complete Freund's Adjuvant (CFA)-induced inflammatory pain model. After CFA injection, P2RY14 was upregulated in primary somatosensory cortex of hindlimb (S1HL). EA, not sham EA, alleviated the nociceptive thermal hyperalgesia and reduced the upregulation of P2RY14 of CFA mice. Injection of P2RY14 agonist uridine diphosphate glucose (UDPG) into bilateral S1HL reversed EA-induced analgesia. Our results demonstrate that EA-induced analgesia of CFA-induced pain can be achieved by downregulation of P2RY14 in the S1HL.

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“…Besides the well-known competitive endogenous RNA (ceRNA) mechanism (lncRNA-miRNA-mRNA networks), which majorly takes place in the cytoplasm, lncRNA-RBP networks have gained increasing attention in their role in different diseases, which takes place in the cell nucleus [8,36]. For example, lncRNA UC.25 interacts with signal transducers and activators of transcription1 (STAT1) to regulate the expression of the P2Y 14 receptor in spinal microglia, promoting diabetic neuropathic pain [37]. In this study, FISH and IF staining demonstrated that lncRNA 4930544M13Rik-201 was expressed majorly in the nucleus of TG neurons.…”

Section: Discussionmentioning

confidence: 99%

LncRNA 4930544M13Rik-201 regulates CACNA2D1 expression via interacting with hnRNPA2B1 to promote neuropathic pain following nerve injury

Fang,

Liu,

Tang

et al. 2024

Preprint

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Long non-coding RNAs (LncRNAs) have recently been reported to play a crucial role in neuropathic pain (NP) resulting from peripheral nerve injury. However, the underlying mechanisms are not fully elucidated. Here, we investigated the role and mechanism of lncRNA 4930544M13Rik-201, a significantly up-regulated lncRNA in both trigeminal ganglion (TG) and dorsal root ganglion (DRG) following peripheral nerve injury, as determined by previous RNA-sequencing results, in the pathogenesis of trigeminal NP induced by infraorbital nerve chronic constriction injury (CCI-ION) in mice. LncRNA 4930544M13Rik-201 was predominantly located in the nuclei of neurons and significantly upregulated in the TG after CCI-ION. Silencing the expression of 4930544M13Rik-201 alleviated mechanical allodynia induced by CCI-ION, while over-expression of 4930544M13Rik-201 in the TG of the WT mice caused orofacial allodynia. Moreover, calcium voltage-gated channel auxiliary subunit alpha 2 delta 1 (CACNA2D1) was identified as the downstream target of lncRNA 4930544M13Rik-201. Notably, 4930544M13Rik-201 increased the stabilization of Cacna2d1 mRNA and protein expression via interacting with heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). Furthermore, inhibition of CACNA2D1 and silencing of hnRNPA2B1 both alleviated the allodynia induced by CCI-ION and the overexpression of 4930544M13Rik-201. Taken together, these results suggest that 4930544M13Rik-201 plays a critical role in the regulation of trigeminal NP induced by CCI-ION through upregulating Cacna2d1 expression via binding to hnRNPA2B1. These findings have important implications for the development of new therapeutic strategies for the treatment of NP by targeting the 4930544M13Rik-201—hnRNPA2B1—CACNA2D1 axis.

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LncRNA-UC.25 + shRNA Alleviates P2Y14 Receptor–Mediated Diabetic Neuropathic Pain via STAT1

Cited by 8 publications

References 25 publications

Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Electroacupuncture may alleviate inflammatory pain by inhibiting the expression of P2RY14 in the primary somatosensory cortex

LncRNA 4930544M13Rik-201 regulates CACNA2D1 expression via interacting with hnRNPA2B1 to promote neuropathic pain following nerve injury

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