Netrin-1 Contributes to Myelinated Afferent Fiber Sprouting and Neuropathic Pain

Wu, Cai; Yuan, Xiao; Gao, Fang; Li, Hong Ping; Cao, Jie; Liu, Yan Shen; Yu, Wei; Tian, Bo; Meng, Xiang; Shi, Jing; Pan, Hui Lin; Li, Man

doi:10.1007/s12035-015-9482-x

Cited by 29 publications

(34 citation statements)

References 43 publications

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“…(58, 59) Netrin-1/DCC interactions also play a role in pain processing in the spinal cord in animal models of mechanical allodynia. (56) Taken together, these findings suggest nociceptive and/or neuropathic mechanisms connecting lumbar intervertebral disc degeneration (including disc herniation) with CBP.…”

Section: Discussionmentioning

confidence: 75%

“…(55) Interactions between DCC and netrin-1 are among the best-studied axonal guidance processes, with key roles during development and in adulthood, and they also affect angiogenesis. (56, 57) Increased expression of netrin-1 and DCC occurs in degenerate human intervertebral discs compared to healthy control discs, and in nucleus pulposus compared to annulus fibrosis. (58) Netrin-1/DCC might therefore mediate neurovascular ingrowth into the intervertebral disc, which has long been implicated as a possible mechanism of chronic discogenic back pain.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

Suri

Palmer

Tsepilov

et al. 2018

Preprint

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OBJECTIVES To conduct a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). METHODS Adults of European ancestry were included from 16 cohorts in Europe and North America. CBP cases were defined as those reporting back pain present for >3-6 months; non-cases were included as comparisons (“controls”). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10−8. Suggestive (p<5×10−7) and genome-wide significant (p<5×10−8) variants were carried forward for replication or further investigation in an independent sample. RESULTS The discovery sample was comprised of 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p=7.2×10−10). This was subsequently replicated in an independent sample of 283,752 subjects, including 50,915 cases (OR 1.06, p=5.3×10−11), and exceeded genome-wide significance in joint meta-analysis (OR=1.07, p=4.5×10−19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p=4.4×10−13), and an intronic variant, rs4384683, in DCC (OR 0.97, p=2.4×10−10). DISCUSSION In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

Suri

Palmer

Tsepilov

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…On the other hand, the osteoclastic resorption may also create an acidic environment in subchondral bone that peripherally sensitizes the nociceptive neurons. Moreover, netrin-1 was also found to activate TRPV1 in dorsal horn neurons (80). Thus, it is possible that netrin-1 itself could also peripherally sensitize nociceptive neurons.…”

Section: Discussionmentioning

confidence: 98%

Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain

Zhu

Zhen

et al. 2019

Journal of Clinical Investigation

307

312

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“…The sections were cut at 20 µm on a cryostat, which were mounted onto gelatin-coated slides and air dried overnight. 24 …”

Section: Methodsmentioning

confidence: 99%

Activation and expression of μ-calpain in dorsal root contributes to RTX-induced mechanical allodynia

Yuan

Gao

et al. 2017

Mol Pain

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BackgroundCalpain is a calcium-dependent cysteine protease, and inhibition of calpain by pre-treatment with MDL28170 attenuated the rat mechanical allodynia in a variety of pain models. Postherpetic neuralgia (Shingles) is a neuropathic pain conditioned with the presence of profound mechanical allodynia. Systemic injection of resiniferatoxin can reproduce the clinical symptoms of postherpetic neuralgia. In this study, we determined to study whether activation of calpain contributes to cleave the myelin basic protein of dorsal root and is involved in resiniferatoxin-induced mechanical allodynia of postherpetic neuralgia animal model.ResultsResiniferatoxin up-regulated the expression and activation of µ-calpain in dorsal root. The expression of µ-calpain was located in Schwann cell of dorsal root, and resiniferatoxin increased the expression of µ-calpain in Schwann cell in L4–L6 dorsal root at six weeks after injection. Resiniferatoxin also induced myelin basic protein degradation in L4–L6 dorsal root at six weeks after injection. Moreover, intraperitoneal injection of calpain inhibitor MDL28170 prevented the degradation of myelin basic protein and then reduced the sprouting of myelinated afferent fibers into spinal lamina II, thus relieving resiniferatoxin-induced mechanical allodynia.ConclusionsUp-regulation and activation of µ-calpain located in Schwann cell may be the mechanism underlying resiniferatoxin-mediated proteolysis of myelin basic protein in dorsal root. Calpain inhibitor MDL28170 prevents resiniferatoxin-induced sprouting of myelinated afferent fibers and mechanical allodynia through inhibition of degradation of the myelin basic protein in dorsal root. Our results indicate that inhibition of pathological µ-calpain activation may present an interesting novel drug target in the treatment of postherpetic neuralgia.

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Netrin-1 Contributes to Myelinated Afferent Fiber Sprouting and Neuropathic Pain

Cited by 29 publications

References 43 publications

Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain

Activation and expression of μ-calpain in dorsal root contributes to RTX-induced mechanical allodynia

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