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Open Access 01-12-2024 | Neuropathic Pain | Research

LncRNA Anxa10-203 enhances Mc1r mRNA stability to promote neuropathic pain by recruiting DHX30 in the trigeminal ganglion

Authors: YaJing Liu, Fei Liu, YiKe Li, YueLing Li, YuHeng Feng, JiaShuo Zhao, Cheng Zhou, ChunJie Li, JieFei Shen, YanYan Zhang

Published in: The Journal of Headache and Pain | Issue 1/2024

Abstract

Background

Trigeminal nerve injury is one of the most serious complications in oral clinics, and the subsequent chronic orofacial pain is a consumptive disease. Increasing evidence demonstrates long non-coding RNAs (lncRNAs) play an important role in the pathological process of neuropathic pain. This study aims to explore the function and mechanism of LncRNA Anxa10-203 in the development of orofacial neuropathic pain.

Methods

A mouse model of orofacial neuropathic pain was established by chronic constriction injury of the infraorbital nerve (CCI-ION). The Von Frey test was applied to evaluate hypersensitivity of mice. RT-qPCR and/or Western Blot were performed to analyze the expression of Anxa10-203, DHX30, and MC1R. Cellular localization of target genes was verified by immunofluorescence and RNA fluorescence in situ hybridization. RNA pull-down and RNA immunoprecipitation were used to detect the interaction between the target molecules. Electrophysiology was employed to assess the intrinsic excitability of TG neurons (TGNs) in vitro.

Results

Anxa10-203 was upregulated in the TG of CCI-ION mice, and knockdown of Anxa10-203 relieved neuropathic pain. Structurally, Anxa10-203 was located in the cytoplasm of TGNs. Mechanistically, Mc1r expression was positively correlated with Anxa10-203 and was identified as the functional target of Anxa10-203. Besides, Anxa10-203 recruited RNA binding protein DHX30 and formed the Anxa10-203/DHX30 complex to enhance the stability of Mc1r mRNA, resulting in the upregulation of MC1R, which contributed to the enhancement of the intrinsic activity of TGNs in vitro and orofacial neuropathic pain in vivo.

Conclusions

LncRNA Anxa10-203 in the TG played an important role in orofacial neuropathic pain and mediated mechanical allodynia in CCI-ION mice by binding with DHX30 to upregulate MC1R expression.

Graphical Abstract

The up-regulated lncRNA Anxa10-203 in the trigeminal ganglion of CCI-ION mice interacts with DHX30 to contribute to the excitability of TG neurons and orofacial pain by enhancing Mc1r mRNA stability.

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Kohli D, Katzmann G, Benoliel R (1939) Korczeniewska OA (2021) Diagnosis and management of persistent posttraumatic trigeminal neuropathic pain secondary to implant therapy: A review. Journal of the American Dental Association 152:483–490. https://doi.org/10.1016/j.adaj.2020.08.017CrossRef

Jensen TS, Finnerup NB (2014) Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. The Lancet Neurology 13:924–935. https://doi.org/10.1016/S1474-4422(14)70102-4CrossRefPubMed

O’Connor AB (2009) Neuropathic pain: quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics 27:95–112. https://doi.org/10.2165/00019053-200927020-00002CrossRefPubMed

Ghazisaeidi S, Muley MM, Salter MW (2023) Neuropathic Pain: Mechanisms, Sex Differences, and Potential Therapies for a Global Problem. Annu Rev Pharmacol Toxicol 63:565–583. https://doi.org/10.1146/annurev-pharmtox-051421-112259CrossRefPubMed

Żylicz JJ, Bousard A, Žumer K et al (2019) The Implication of Early Chromatin Changes in X Chromosome Inactivation. Cell 176:182-197.e23. https://doi.org/10.1016/j.cell.2018.11.041CrossRefPubMedPubMedCentral

Guttman M, Donaghey J, Carey BW et al (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477:295–300. https://doi.org/10.1038/nature10398CrossRefPubMedPubMedCentralADS

Liu Q, Mai L, Yang S et al (2022) Transcriptional Alterations of Mouse Trigeminal Ganglion Neurons Following Orofacial Inflammation Revealed by Single-Cell Analysis. Front Cell Neurosci 16:885569. https://doi.org/10.3389/fncel.2022.885569CrossRefPubMedPubMedCentral

Wang K, Wang S, Chen Y et al (2021) Single-cell transcriptomic analysis of somatosensory neurons uncovers temporal development of neuropathic pain. Cell Res 31:904–918. https://doi.org/10.1038/s41422-021-00479-9CrossRefPubMedPubMedCentral

Du S, Wu S, Feng X et al (2022) A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression. The Journal of Clinical Investigation 132:e153563. https://doi.org/10.1172/JCI153563CrossRefPubMedPubMedCentral

10.

Zhao X, Tang Z, Zhang H et al (2013) A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat Neurosci 16:1024–1031. https://doi.org/10.1038/nn.3438CrossRefPubMedPubMedCentral

11.

Wen C-H, Berkman T, Li X et al (2023) Effect of intrathecal NIS-lncRNA antisense oligonucleotides on neuropathic pain caused by nerve trauma, chemotherapy, or diabetes mellitus. Br J Anaesth 130:202–216. https://doi.org/10.1016/j.bja.2022.09.027CrossRefPubMed

12.

Fang Z-H, Liao H-L, Tang Q-F et al (2022) Interactions Among Non-Coding RNAs and mRNAs in the Trigeminal Ganglion Associated with Neuropathic Pain. Journal of Pain Research 15:2967–2988. https://doi.org/10.2147/JPR.S382692CrossRefPubMedPubMedCentral

13.

Jonas K, Calin GA, Pichler M (2020) RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer. International Journal of Molecular Sciences 21:E2969. https://doi.org/10.3390/ijms21082969CrossRef

14.

Bosco B, Rossi A, Rizzotto D et al (2021) DHX30 Coordinates Cytoplasmic Translation and Mitochondrial Function Contributing to Cancer Cell Survival. Cancers 13:4412. https://doi.org/10.3390/cancers13174412CrossRefPubMedPubMedCentral

15.

Aa P, E J (2013) DEAD-box helicases as integrators of RNA, nucleotide and protein binding. Biochimica et biophysica acta 1829:. https://doi.org/10.1016/j.bbagrm.2013.02.002

16.

Jung C, Mittler G, Oswald F, Borggrefe T (2013) RNA helicase Ddx5 and the noncoding RNA SRA act as coactivators in the Notch signaling pathway. Biochimica Et Biophysica Acta 1833:1180–1189. https://doi.org/10.1016/j.bbamcr.2013.01.032CrossRefPubMed

17.

Yao H, Brick K, Evrard Y et al (2010) Mediation of CTCF transcriptional insulation by DEAD-box RNA-binding protein p68 and steroid receptor RNA activator SRA. Genes Dev 24:2543–2555. https://doi.org/10.1101/gad.1967810CrossRefPubMedPubMedCentral

18.

Eom T, Muslimov IA, Tsokas P et al (2014) Neuronal BC RNAs cooperate with eIF4B to mediate activity-dependent translational control. The Journal of Cell Biology 207:237–252. https://doi.org/10.1083/jcb.201401005CrossRefPubMedPubMedCentral

19.

Koikov L, Starner RJ, Swope VB et al (2021) Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes. The Journal of Investigative Dermatology 141:1819–1829. https://doi.org/10.1016/j.jid.2020.11.034CrossRefPubMedPubMedCentral

20.

Robinson KC, Kemény LV, Fell GL, et al (2021) Reduced MC4R signaling alters nociceptive thresholds associated with red hair. Sci Adv 7:eabd1310. https://doi.org/10.1126/sciadv.abd1310

21.

Mogil JS, Wilson SG, Chesler EJ et al (2003) The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A 100:4867–4872. https://doi.org/10.1073/pnas.0730053100CrossRefPubMedPubMedCentralADS

22.

Mogil JS, Ritchie J, Smith SB et al (2005) Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. J Med Genet 42:583–587. https://doi.org/10.1136/jmg.2004.027698CrossRefPubMedPubMedCentral

23.

Zorina-Lichtenwalter K, Maixner W, Diatchenko L (2020) Detangling red hair from pain: phenotype-specific contributions from different genetic variants in melanocortin-1 receptor. Pain 161:938–948. https://doi.org/10.1097/j.pain.0000000000001780CrossRefPubMedPubMedCentral

24.

Vrinten DH, Adan RA, Groen GJ, Gispen WH (2001) Chronic blockade of melanocortin receptors alleviates allodynia in rats with neuropathic pain. Anesth Analg 93:1572–1577, table of contents. https://doi.org/10.1097/00000539-200112000-00052

25.

Klusa V, Germane S, Svirskis S et al (2001) The gamma(2)-MSH peptide mediates a central analgesic effect via a GABA-ergic mechanism that is independent from activation of melanocortin receptors. Neuropeptides 35:50–57. https://doi.org/10.1054/npep.2000.0843CrossRefPubMed

26.

Kernisant M, Gear R, Jasmin L et al (2008) Chronic Constriction Injury of the Infraorbital Nerve in the Rat using modified syringe needle. J Neurosci Methods 172:43–47. https://doi.org/10.1016/j.jneumeth.2008.04.013CrossRefPubMedPubMedCentral

27.

Zhang Y-Y, Liu F, Fang Z-H et al (2022) Differential roles of NMDAR subunits 2A and 2B in mediating peripheral and central sensitization contributing to orofacial neuropathic pain. Brain Behav Immun 106:129–146. https://doi.org/10.1016/j.bbi.2022.08.010CrossRefPubMed

28.

Herpin TF, Yu G, Carlson KE et al (2003) Discovery of tyrosine-based potent and selective melanocortin-1 receptor small-molecule agonists with anti-inflammatory properties. J Med Chem 46:1123–1126. https://doi.org/10.1021/jm025600iCrossRefPubMed

29.

Wang J, Yang Y, Liu J et al (2023) Loss of sodium leak channel (NALCN) in the ventral dentate gyrus impairs neuronal activity of the glutamatergic neurons for inflammation-induced depression in male mice. Brain, Behavior, and Immunity 110:13–29. https://doi.org/10.1016/j.bbi.2023.02.013CrossRefPubMed

30.

Kopp F, Mendell JT (2018) Functional Classification and Experimental Dissection of Long Noncoding RNAs. Cell 172:393–407. https://doi.org/10.1016/j.cell.2018.01.011CrossRefPubMedPubMedCentral

31.

Rossi M, Bucci G, Rizzotto D et al (2019) LncRNA EPR controls epithelial proliferation by coordinating Cdkn1a transcription and mRNA decay response to TGF-β. Nat Commun 10:1969. https://doi.org/10.1038/s41467-019-09754-1CrossRefPubMedPubMedCentralADS

32.

Araújo-Filho HG, Pereira EWM, Campos AR et al (2018) Chronic orofacial pain animal models - progress and challenges. Expert Opin Drug Discovery 13:949–964. https://doi.org/10.1080/17460441.2018.1524458CrossRef

33.

Mogil JS (2009) Animal models of pain: progress and challenges. Nat Rev Neurosci 10:283–294. https://doi.org/10.1038/nrn2606CrossRefPubMed

34.

Sung E-S, Kwon H-K, Shin S-C, et al (2021) Application of an Intraoperative Neuromonitoring System Using a Surface Pressure Sensor in Parotid Surgery: A Rabbit Model Study. Clin Exp Otorhinolaryngol 14:131–136. https://doi.org/10.21053/ceo.2019.01900

35.

Leamy KA, Assmann SM, Mathews DH, Bevilacqua PC (2016) Bridging the gap between in vitro and in vivo RNA folding. Q Rev Biophys 49:e10. https://doi.org/10.1017/S003358351600007XCrossRefPubMedPubMedCentral

36.

Sun L-Z, Zhang D, Chen S-J (2017) Theory and Modeling of RNA Structure and Interactions with Metal Ions and Small Molecules. Annu Rev Biophys 46:227–246. https://doi.org/10.1146/annurev-biophys-070816-033920CrossRefPubMedPubMedCentral

37.

Liu Z, Wang J, Cheng H et al (2018) Cryo-EM Structure of Human Dicer and Its Complexes with a Pre-miRNA Substrate. Cell 173:1549–1550. https://doi.org/10.1016/j.cell.2018.05.031CrossRefPubMed

38.

Jarmoskaite I, Russell R (2014) RNA helicase proteins as chaperones and remodelers. Annu Rev Biochem 83:697–725. https://doi.org/10.1146/annurev-biochem-060713-035546CrossRefPubMedPubMedCentral

39.

Jung J, Lifland AW, Zurla C et al (2013) Quantifying RNA–protein interactions in situ using modified-MTRIPs and proximity ligation. Nucleic Acids Res 41:e12. https://doi.org/10.1093/nar/gks837CrossRefPubMed

40.

Mannucci I, Dang NDP, Huber H et al (2021) Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders. Genome Med 13:90. https://doi.org/10.1186/s13073-021-00900-3CrossRefPubMedPubMedCentral

41.

D L, C S, S K, et al (2017) De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder. American journal of human genetics 101:. https://doi.org/10.1016/j.ajhg.2017.09.014

42.

Rizzotto D, Zaccara S, Rossi A et al (2020) Nutlin-Induced Apoptosis Is Specified by a Translation Program Regulated by PCBP2 and DHX30. Cell Rep 30:4355-4369.e6. https://doi.org/10.1016/j.celrep.2020.03.011CrossRefPubMedPubMedCentral

43.

Hilliker A, Gao Z, Jankowsky E, Parker R (2011) The DEAD-box protein Ded1 modulates translation by the formation and resolution of an eIF4F-mRNA complex. Mol Cell 43:962–972. https://doi.org/10.1016/j.molcel.2011.08.008CrossRefPubMedPubMedCentral

44.

Chelakkot VS, Thomas K, Romigh T et al (2023) MC1R signaling through the cAMP-CREB/ATF-1 and ERK-NFκB pathways accelerates G1/S transition promoting breast cancer progression. NPJ Precis Oncol 7:85. https://doi.org/10.1038/s41698-023-00437-1CrossRefPubMedPubMedCentral

45.

René F, Muller A, Jover E et al (1998) Melanocortin receptors and delta-opioid receptor mediate opposite signalling actions of POMC-derived peptides in CATH.a cells. Eur J Neurosci 10:1885–1894. https://doi.org/10.1046/j.1460-9568.1998.00199.xCrossRefPubMed

46.

Hu S-J, Song X-J, Greenquist KW et al (2001) Protein kinase A modulates spontaneous activity in chronically compressed dorsal root ganglion neurons in the rat. Pain 94:39–46. https://doi.org/10.1016/S0304-3959(01)00339-6CrossRefPubMed

47.

Pierre S, Eschenhagen T, Geisslinger G, Scholich K (2009) Capturing adenylyl cyclases as potential drug targets. Nat Rev Drug Discov 8:321–335. https://doi.org/10.1038/nrd2827CrossRefPubMed

48.

Vrinten DH, Gispen WH, Kalkman CJ, Adan RAH (2003) Interaction between the Spinal Melanocortin and Opioid Systems in a Rat Model of Neuropathic Pain. Anesthesiology 99:449–454. https://doi.org/10.1097/00000542-200308000-00028CrossRefPubMed

49.

Zhou Y, Chawla MK, Rios-Monterrosa JL et al (2021) Aged Brains Express Less Melanocortin Receptors, Which Correlates with Age-Related Decline of Cognitive Functions. Molecules (Basel, Switzerland) 26:6266. https://doi.org/10.3390/molecules26206266CrossRefPubMed

50.

Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578. https://doi.org/10.1038/nn1455CrossRefPubMed

51.

Vrinten DH, Gispen WH, Groen GJ, Adan RAH (2000) Antagonism of the Melanocortin System Reduces Cold and Mechanical Allodynia in Mononeuropathic Rats. J Neurosci 20:8131–8137. https://doi.org/10.1523/JNEUROSCI.20-21-08131.2000CrossRefPubMedPubMedCentral

Title: LncRNA Anxa10-203 enhances Mc1r mRNA stability to promote neuropathic pain by recruiting DHX30 in the trigeminal ganglion
Authors: YaJing Liu
Fei Liu
YiKe Li
YueLing Li
YuHeng Feng
JiaShuo Zhao
Cheng Zhou
ChunJie Li
JieFei Shen
YanYan Zhang
Publication date: 01-12-2024
Publisher: Springer Milan
Keyword: Neuropathic Pain
Published in: The Journal of Headache and Pain / Issue 1/2024
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-024-01733-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

LncRNA Anxa10-203 enhances Mc1r mRNA stability to promote neuropathic pain by recruiting DHX30 in the trigeminal ganglion

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

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