A variety of studies have proposed that transient receptor potential vanilloid 1 (TRPV1) is involved in the progression of multiple diseases, including neuropathic pain. Although increased expression of TRPV1 in chronic constriction injury was described earlier, the underlying regulatory mechanisms of TRPV1 in neuropathic pain remain largely unknown. In our study, we constructed a chronic constriction injury (CCI) rat model to deeply analyze the mechanisms underlying TRPV1. RT-qPCR-indicated TRPV1 mRNA and protein expression were extremely upregulated in CCI rat dorsal spinal cord tissues. Then, TRPV1 was corroborated to interact with N-terminal EF-hand Ca2+-binding protein 2 (NECAB2). The mRNA and protein levels of NECAB2 were increased in CCI tissues. Moreover, TRPV1 and NECAB2 together regulated nociceptive procession-associated protein metabotropic glutamate receptor 5 (mGluR5), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and Ca2+ in isolated microglia of CCI rats. Moreover, TRPV1 upregulation apparently increased mechanical allodynia and thermal hyperalgesia as well as the expression of inflammation-associated genes (COX-2, TNF-α, and IL-6). In addition, downregulation of NECAB2 significantly decreased mechanical allodynia and thermal hyperalgesia as well as the expression of COX-2, TNF-α, and IL-6. Furthermore, TRPV1 was confirmed to be a downstream target of miR-338-3p. TRPV1 overexpression abolished the inhibitory effect by miR-338-3p elevation on neuropathic pain development. In summary, this study proved TRPV1, targeted by miR-338-3p, induced neuropathic pain by interacting with NECAB2, which provides a potential therapeutic target for neuropathic pain treatment.
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Bautista DM, Wilson SR, Hoon MA (2014) Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci 17:175–182. https://doi.org/10.1038/nn.3619
Cai W, Zhang Y, Liu Y, Liu H, Zhang Z, Su Z (2019) Effects of miR-150 on neuropathic pain process via targeting AKT3. Biochem Biophys Res Commun 517:532–537. https://doi.org/10.1016/j.bbrc.2019.07.061
Clapham DE (2003) TRP channels as cellular sensors. Nature 426:517–524. https://doi.org/10.1038/nature02196
Cohen SP, Mao J (2014) Neuropathic pain: mechanisms and their clinical implications. BMJ (Clinical Research Ed) 348:f7656. https://doi.org/10.1136/bmj.f7656
Finnerup NB et al (2016) Neuropathic pain: an updated grading system for research and clinical practice. Pain 157:1599–1606. https://doi.org/10.1097/j.pain.0000000000000492
Flynn R, Chapman K, Iftinca M, Aboushousha R, Varela D, Altier C (2014) Targeting the transient receptor potential vanilloid type 1 (TRPV1) assembly domain attenuates inflammation-induced hypersensitivity. J Biol Chem 289:16675–16687. https://doi.org/10.1074/jbc.M114.558668
Huang LE, Guo SH, Thitiseranee L, Yang Y, Zhou YF, Yao YX (2018) N-methyl D-aspartate receptor subtype 2B antagonist, Ro 25-6981, attenuates neuropathic pain by inhibiting postsynaptic density 95 expression. Sci Rep 8:7848. https://doi.org/10.1038/s41598-018-26209-7
Jara-Oseguera A, Bae C, Swartz KJ (2016) An external sodium ion binding site controls allosteric gating in TRPV1 channels. eLife 5 https://doi.org/10.7554/eLife.13356
Jiang M et al (2019) Inflammation up-regulates cochlear expression of TRPV1 to potentiate drug-induced hearing loss. Sci Adv 5:eaaw1836. https://doi.org/10.1126/sciadv.aaw1836
Lema MJ, Foley KM, Hausheer FH (2010) Types and epidemiology of cancer-related neuropathic pain: the intersection of cancer pain and neuropathic pain. Oncologist 15(Suppl 2):3–8. https://doi.org/10.1634/theoncologist.2009-S505
Li T et al (2019) Inhibition of MicroRNA-15a/16 expression alleviates neuropathic pain development through upregulation of G protein-coupled receptor kinase 2. Biomol Ther 27:414–422. https://doi.org/10.4062/biomolther.2018.073
Liu H, Sun Q, Wan C, Li L, Zhang L, Chen Z (2014) MicroRNA-338-3p regulates osteogenic differentiation of mouse bone marrow stromal stem cells by targeting Runx2 and Fgfr2. J Cell Physiol 229:1494–1502. https://doi.org/10.1002/jcp.24591
Liu J, Cao L, Feng Y, Li Y, Li T (2017) MiR-338-3p inhibits TNF-alpha-induced lipogenesis in human sebocytes. Biotechnol Lett 39:1343–1349. https://doi.org/10.1007/s10529-017-2369-3
Luo J et al (2018) Zinc inhibits TRPV1 to alleviate chemotherapy-induced neuropathic pain. J Neurosci 38:474–483. https://doi.org/10.1523/jneurosci.1816-17.2017
Malek N, Pajak A, Kolosowska N, Kucharczyk M, Starowicz K (2015) The importance of TRPV1-sensitisation factors for the development of neuropathic pain. Mol Cell Neurosci 65:1–10. https://doi.org/10.1016/j.mcn.2015.02.001
Marrone MC et al. (2017) TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice Nature communications 8:15292 doi:https://doi.org/10.1038/ncomms15292
Mohr AM, Mott JL (2015) Overview of microRNA biology. Semin Liver Dis 35:3–11. https://doi.org/10.1055/s-0034-1397344
Sudhof TC (2012) The presynaptic active zone. Neuron 75:11–25. https://doi.org/10.1016/j.neuron.2012.06.012
Sun F et al (2018) miR-338-3p functions as a tumor suppressor in gastric cancer by targeting PTP1B. Cell Death Dis 9:522. https://doi.org/10.1038/s41419-018-0611-0
van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N (2014) Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 155:654–662. https://doi.org/10.1016/j.pain.2013.11.013
Yan XT et al (2018) XIST accelerates neuropathic pain progression through regulation of miR-150 and ZEB1 in CCI rat models. J Cell Physiol 233:6098–6106. https://doi.org/10.1002/jcp.26453
Zhan LY et al (2018) Overexpression of miR-381 relieves neuropathic pain development via targeting HMGB1 and CXCR4. Biomed Pharmacother 107:818–823. https://doi.org/10.1016/j.biopha.2018.08.053
Zhang MD et al (2014) Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury. Proc Natl Acad Sci U S A 111:E1149–E1158. https://doi.org/10.1073/pnas.1402318111
Zhang MD et al (2016) Comparative anatomical distribution of neuronal calcium-binding protein (NECAB) 1 and −2 in rodent and human spinal cord. Brain Struct Funct 221:3803–3823. https://doi.org/10.1007/s00429-016-1191-3
Zhang Y, Su Z, Liu HL, Li L, Wei M, Ge DJ, Zhang ZJ (2018) Effects of miR-26a-5p on neuropathic pain development by targeting MAPK6 in in CCI rat models. Biomed Pharmacother 107:644–649. https://doi.org/10.1016/j.biopha.2018.08.005
Zhong L, Xiao W, Wang F, Liu J, Zhi LJ (2019) miR-21-5p inhibits neuropathic pain development via directly targeting C-C motif ligand 1 and tissue inhibitor of metalloproteinase-3. J Cell Biochem 120:16614–16623. https://doi.org/10.1002/jcb.28920
We appreciate the support of Taizhou Hospital, Wenzhou Medical University, Zhejiang Province.
The Institutional Animal Care and Use Committee of Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University (Zhejiang, China), approved the protocols for our study.
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Ma, Y., Deng, Q., Li, S. et al. TRPV1, Targeted by miR-338-3p, Induces Neuropathic Pain by Interacting with NECAB2. J Mol Neurosci (2020). https://doi.org/10.1007/s12031-020-01626-4
- Neuropathic pain