Up-regulation of Cathepsin G in the Development of Chronic Postsurgical Pain

Liu, Xiao Dong; Tian, Yuanyuan; Meng, Zhaohai; Chen, Yan; Ho, Idy H. T.; Choy, Kwong Wai; Lichtner, Peter; Wong, Sunny H.; Yu, Jun; Gin, Tony; Wu, William Ka Kei; Chen, Cheng; Chan, Matthew T. V.

doi:10.1097/aln.0000000000000828

Cited by 28 publications

(21 citation statements)

References 35 publications

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“…Severe acute postoperative pain increases the risk of chronic postsurgical pain, and this may introduce bias. 7 However, our previous study showed that intraoperative nitrous oxide administration has no effect on early postoperative analgesia. 17 Finally, we did not adjust subgroup analyses for multiple testing, and this may increase type I error.…”

Section: Discussionmentioning

confidence: 93%

Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial

Chan¹,

Peyton²,

Myles³

et al. 2016

British Journal of Anaesthesia

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Section: Discussionmentioning

confidence: 93%

Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial

Chan¹,

Peyton²,

Myles³

et al. 2016

British Journal of Anaesthesia

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“…To test this hypothesis, we first evaluated expression of sortilin in CFA-induced chronic inflammatory pain model. We previously reported significantly increased thermal hyperalgesia after intraplantar injection of CFA 22. Classical signs, including edema and erythema of the left hind paws, with CFA injection were observed within 1 h and throughout the entire experiment (Supplementary Figure S1).…”

Section: Resultsmentioning

confidence: 77%

A Novel Peptide Interfering with proBDNF-Sortilin Interaction Alleviates Chronic Inflammatory Pain

Liu

Zou

et al. 2019

Theranostics

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Rationale: Brain-derived neurotrophic factor (BDNF) is a key mediator in the development of chronic pain. Sortilin is known to interact with proBDNF and regulate its activity-dependent secretion in cortical neurons. In a rat model of inflammatory pain with intraplantar injection of complete Freund's adjuvant (CFA), we examined the functional role of proBDNF-sortilin interaction in dorsal root ganglia (DRG). Methods: Expression and co-localization of BDNF and sortilin were determined by immunofluorescence. ProBDNF-sortilin interaction interface was mapped using co-immunoprecipitation and bimolecular fluorescence complementation assay. The analgesic effect of intrathecal injection of a synthetic peptide interfering with proBDNF-sortilin interaction was measured in the CFA model. Results: BDNF and sortilin were co-localized and their expression was significantly increased in ipsilateral L4/5 DRG upon hind paw CFA injection. In vivo adeno-associated virus-mediated knockdown of sortilin-1 in L5 DRG alleviated pain-like responses. Mapping by serial deletions in the BDNF prodomain indicated that amino acid residues 71-100 supported the proBDNF-sortilin interaction. A synthetic peptide identical to amino acid residues 89-98 of proBDNF, as compared with scrambled peptide, was found to interfere with proBDNF-sortilin interaction, inhibit activity-dependent release of BDNF in vitro and reduce CFA-induced mechanical allodynia and heat hyperalgesia in vivo . The synthetic peptide also interfered with capsaicin-induced phosphorylation of extracellular signal-regulated kinases in ipsilateral spinal cord of CFA-injected rats. Conclusions: Sortilin-mediated secretion of BDNF from DRG neurons contributes to CFA-induced inflammatory pain. Interfering with proBDNF-sortilin interaction reduced activity-dependent release of BDNF and might serve as a therapeutic approach for chronic inflammatory pain.

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“…Mpo has been shown by gene knockout to exacerbate secondary injury after SCI (Kubota et al, 2012). Ctsg is a pronociceptive mediator in the spinal cord (Liu et al, 2015), as is carbonic anhydrases (gene Car1 ) (Asiedu et al, 2010). Neutrophil elastase, which is released by activated neutrophils, is reported to be a key mediator of secondary pathogenesis in SCI (Semple et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Brainstem-Evoked Transcription of Defensive Genes After Spinal Cord Injury

Jermakowicz

Carballosa-Gautam

Vitores

et al. 2019

Front. Cell. Neurosci.

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The spinal cord after injury shows altered transcription in numerous genes. We tested in a pilot study whether the nucleus raphé magnus, a descending serotonergic brainstem region whose stimulation improves recovery after incomplete spinal cord injury (SCI), can influence these transcriptional changes. Rats received 2 h of low-frequency electrical stimulation in the raphé magnus 3 days after an impact contusion at segment T8. Comparison groups lacked injuries or activated stimulators or both. Immediately following stimulation, spinal cords were extracted, their RNA transcriptome sequenced, and differential gene expression quantified. Confirming many previous studies, injury primarily increased inflammatory and immune transcripts and decreased those related to lipid and cholesterol synthesis and neuronal signaling. Stimulation plus injury, contrasted with injury alone, caused significant changes in 43 transcripts (39 increases, 4 decreases), all protein-coding. Injury itself decreased only four of these 43 transcripts, all reversed by stimulation, and increased none of them. The non-specific 5-HT7 receptor antagonist pimozide reversed 25 of the 43 changes. Stimulation in intact rats principally caused decreases in transcripts related to oxidative phosphorylation, none of which were altered by stimulation in injury. Gene ontology (biological process) annotations comparing stimulation with either no stimulation or pimozide treatment in injured rats highlighted defense responses to lipopolysaccharides and microorganisms, and also erythrocyte development and oxygen transport (possibly yielding cellular oxidant detoxification). Connectivity maps of human orthologous genes generated in the CLUE database of perturbagen-response transcriptional signatures showed that drug classes whose effects in injured rats most closely resembled stimulation without pimozide include peroxisome proliferator-activated receptor agonists and angiotensin receptor blockers, which are reportedly beneficial in SCI. Thus the initial transcriptional response of the injured spinal cord to raphé magnus stimulation is upregulation of genes that in various ways are mostly protective, some probably located in recently arrived myeloid cells.

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Up-regulation of Cathepsin G in the Development of Chronic Postsurgical Pain

Abstract: This study demonstrated that CTSG is a pronociceptive mediator in both animal model and human study. CTSG represents a new target for pain control and a potential marker to predict patients who are prone to develop chronic pain after surgery.

Cited by 28 publications

References 35 publications

Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial

Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial

A Novel Peptide Interfering with proBDNF-Sortilin Interaction Alleviates Chronic Inflammatory Pain

Brainstem-Evoked Transcription of Defensive Genes After Spinal Cord Injury

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