Long Noncoding RNA H19 in the Injured Dorsal Root Ganglion Contributes to Peripheral Nerve Injury-Induced Pain Hypersensitivity

Wen, Jing; Yang, Yong; Wu, Shaogen; Wei, Guihua; Jia, Shushan; Hannaford, Stephen; Tao, Yuan‐Xiang

doi:10.31480/2330-4871/110

Cited by 10 publications

(7 citation statements)

References 42 publications

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“…The upregulated DRG NT3 contributes to the paclitaxel-induced CINP likely through the TrkC-mediated increase of CCL2 in DRG neurons. Systemic administration of paclitaxel and oxaliplatin increased the expression of DRG CCL2 (Al-Mazidi et al, 2018 ; Curry et al, 2018 ; Illias et al, 2018 ; Wen et al, 2020 , 2023 ; Zhang et al, 2016a ). We also showed a robust increase in the level of CCL2 in DRGs on days 14 and 28 after the first paclitaxel injection.…”

Section: Discussionmentioning

confidence: 99%

NT-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons

Sharma,

Feng,

Wang

et al. 2024

EMBO Rep

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Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), and the therapeutic options for managing CINP are limited. Here, we show that systemic paclitaxel administration upregulates the expression of neurotrophin-3 (Nt3) mRNA and NT3 protein in the neurons of dorsal root ganglia (DRG), but not in the spinal cord. Blocking NT3 upregulation attenuates paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in male and female mice. Conversely, mimicking this increase produces enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naive male and female mice. Mechanistically, NT3 triggers tropomyosin receptor kinase C (TrkC) activation and participates in the paclitaxel-induced increases of C–C chemokine ligand 2 (Ccl2) mRNA and CCL2 protein in the DRG. Given that CCL2 is an endogenous initiator of CINP and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNAs in DRG neurons, NT3 likely contributes to CINP through TrkC-mediated activation of the Ccl2 gene in DRG neurons. NT3 may be thus a potential target for CINP treatment.

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Section: Discussionmentioning

confidence: 99%

NT-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons

Sharma,

Feng,

Wang

et al. 2024

EMBO Rep

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“…The preclinical mouse model of SNL-induced neuropathic pain was also performed as described previously (41)(42)(43)(44). Briefly, after the mice were anesthetized with 2% isoflurane, the unilateral L4 transverse process was identified and removed.…”

Section: Methodsmentioning

confidence: 99%

“…DRG microinjection. DRG microinjection was performed following the protocols established in our previous studies (41)(42)(43)(44). Briefly, after the mice were anesthetized as described above, a midline incision was made in the lower lumbar back region.…”

Section: Methodsmentioning

confidence: 99%

“…Behavioral tests. The evoked pain tests, including mechanical, heat, and cold assessments, were conducted in order at 1-hour intervals before viral microinjection or surgery and at various points after surgery, following the previously described protocols (41)(42)(43)(44). The CPP test was conducted on day 14 or 21 after surgery, and the locomotor functional test was performed before tissue collection.…”

Section: Methodsmentioning

confidence: 99%

“…The CPP test was conducted following our previous studies with minor modifications (41)(42)(43)(44). Briefly, an apparatus with 2 Plexiglas chambers connected by an internal door (Med Associates Inc.) was used.…”

Section: Methodsmentioning

confidence: 99%

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ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain

Wang,

Zuo,

Feng

et al. 2024

JCI Insight

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Peripheral nerve injury–induced neuronal hyperactivity in the dorsal root ganglion (DRG) participates in neuropathic pain. The calcium-activated potassium channel subfamily N member 1 (KCNN1) mediates action potential afterhyperpolarization (AHP) and gates neuronal excitability. However, the specific contribution of DRG KCNN1 to neuropathic pain is not yet clear. We report that chronic constriction injury (CCI) of the unilateral sciatic nerve or unilateral ligation of the fourth lumbar nerve produced the downregulation of Kcnn1 mRNA and KCNN1 protein in the injured DRG. This downregulation was partially attributed to a decrease in DRG estrogen-related receptor gamma (ESRRG), a transcription factor, which led to reduced binding to the Kcnn1 promoter. Rescuing this downregulation prevented CCI-induced decreases in total potassium voltage currents and AHP currents, reduced excitability in the injured DRG neurons, and alleviated CCI-induced development and maintenance of nociceptive hypersensitivities, without affecting locomotor function and acute pain. Mimicking the CCI-induced DRG KCNN1 downregulation resulted in augmented responses to mechanical, heat, and cold stimuli in naive mice. Our findings indicate that ESRRG-controlled downregulation of DRG KCNN1 is likely essential for the development and maintenance of neuropathic pain. Thus, KCNN1 may serve as a potential target for managing this disorder.

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C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

Cao

Jiang

et al. 2022

Mol Neurobiol

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Nerve trauma-induced toll-like receptor 7 (TLR7) expression level increases in primary sensory neurons in injured dorsal root ganglion (DRG) avails to neuropathic pain, but the reason is still unknown. In the current study, we showed that unilateral lumbar 4 (L4) spinal nerve ligation (SNL) upregulated CCAAT/enhancer-binding protein-β (C/EBPβ) expression in ipsilateral L4 DRG. Preventing this elevation attenuated the SNL-induced upregulation of TLR7 in the ipsilateral L4 DRG and inhibited cold/thermal hyperalgesia and mechanical allodynia. In injected DRG, mimicking nerve trauma-induced C/EBPβ upregulation increased TLR7 levels, augmented responses to cold/thermal/mechanical stimuli, and caused ipsilateral spontaneous pain with no SNL. Mechanistically, SNL upregulated binding of increased C/EBPβ to Tlr7 promoter in ipsilateral L4 DRG. Accorded that C/EBPβ could trigger the activation of Tlr7 promoter and co-expressed with Tlr7 mRNA in individual DRG neurons, our findings strongly suggest the role of C/EBPβ in nerve trauma-mediated TLR7 upregulation in injured primary sensory neurons.

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Long Noncoding RNA H19 in the Injured Dorsal Root Ganglion Contributes to Peripheral Nerve Injury-Induced Pain Hypersensitivity

Cited by 10 publications

References 42 publications

NT-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons

NT-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons

ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain

C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

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