Glycemia-dependent Nuclear Factor κB Activation Contributes to Mechanical Allodynia in Rats with Chronic Postischemia Pain

Ross-Huot, Marie-Christine; Laferrière, André; Khorashadi, Mina; Coderre, Terence J.

doi:10.1097/aln.0b013e318299980c

Cited by 7 publications

(8 citation statements)

References 37 publications

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“…Studies showed that nuclear factor-κB (NF-κB), as a critical transcriptional factor, played critical roles in the induction and development of chronic pain. 13 – 15 Activation of NF-κB participated in nerve injury or inflammation-induced pathological pain. 16 , 17 Recent studies showed that NF-κB is also involved in chemotherapy-induced chronic pain.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of CX3CL1 mediated by NF-κB activation in dorsal root ganglion contributes to peripheral sensitization and chronic pain induced by oxaliplatin administration

et al. 2017

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Painful peripheral neuropathy is a severe side effect in oxaliplatin therapy that compromises cancer patients' quality of life. However, its underlying pathogenic mechanisms remain largely unknown. Here, we found that intraperitoneal consecutive administration of oxaliplatin significantly increased excitability of small diameter dorsal root ganglion neurons and induced thermal hyperalgesia in rats. Furthermore, the CX3CL1 expression was significantly increased after oxaliplatin treatment, and intrathecal injection of a neutralizing antibody against CX3CL1 markedly attenuated the enhanced excitability of dorsal root ganglion neurons and thermal hyperalgesia. Importantly, the upregulated CX3CL1 is mediated by the NF-κB signaling pathway, as inhibition of NF-κB p65 activation with pyrrolidine dithiocarbamate or p65 siRNA inhibited the upregulation of CX3CL1, the enhanced excitability of dorsal root ganglion neurons, and thermal hyperalgesia induced by oxaliplatin. Further studies with chromatin immunoprecipitation found that oxaliplatin treatment increased the recruitment of NF-κB p65 to the CX3Cl1 promoter region. Our results suggest that upregulation of CX3CL1 in dorsal root ganglion mediated by NF-κB activation contributes to the peripheral sensitization and chronic pain induced by oxaliplatin administration.

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Section: Introductionmentioning

confidence: 99%

Upregulation of CX3CL1 mediated by NF-κB activation in dorsal root ganglion contributes to peripheral sensitization and chronic pain induced by oxaliplatin administration

et al. 2017

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“…Although NF-κB is seemingly involved in BMSC-induced protection as shown above, it is well known that activation of NF-κB pathway contributes to pro-inflammatory responses, characterized by induction of pro-inflammatory cytokines such as IL-1β (Ghosh et al, 1998 ; Bonizzi and Karin, 2004 ). Accordingly, NF-κB-involved signaling plays a role in enhanced pain sensitivity (Ross-Huot et al, 2013 ; Zhou et al, 2018 ). In our inhibitor only experiment, BAY 11-7082 (25 pmol/0.5 μl) was injected into the RVM at 7 days after TL and BMSCs were not infused.…”

Section: Resultsmentioning

confidence: 99%

“…It is well known that NFκB activation is pro-inflammatory, characterized by induction of pro-inflammatory cytokines (Ghosh et al, 1998 ; Bonizzi and Karin, 2004 ). Studies have shown contribution of NF-κB to persistent pain (de Mos et al, 2009 ; Ross-Huot et al, 2013 ; Borghi et al, 2017 ). Thus, under persistent pain conditions without BMSC treatment, suppressing NF-κB should attenuate hyperalgesia (Ledeboer et al, 2005 ; Zhou et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

NF-KappaB Pathway Is Involved in Bone Marrow Stromal Cell-Produced Pain Relief

Guo

Imai

Yang

et al. 2018

Front. Integr. Neurosci.

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Bone marrow stromal cells (BMSCs) produce long-lasting attenuation of pain hypersensitivity. This effect involves BMSC’s ability to interact with the immune system and activation of the endogenous opioid receptors in the pain modulatory circuitry. The nuclear factor kappa B (NF-κB) protein complex is a key transcription factor that regulates gene expression involved in immunity. We tested the hypothesis that the NF-κB signaling plays a role in BMSC-induced pain relief. We focused on the rostral ventromedial medulla (RVM), a key structure in the descending pain modulatory pathway, that has been shown to play an important role in BMSC-produced antihyperalgesia. In Sprague-Dawley rats with a ligation injury of the masseter muscle tendon (TL), BMSCs (1.5 M/rat) from donor rats were infused i.v. at 1 week post-TL. P65 exhibited predominant neuronal localization in the RVM with scattered distribution in glial cells. At 1 week, but not 8 weeks after BMSC infusion, western blot and immunostaining showed that p65 of NF-κB was significantly increased in the RVM. Given that chemokine signaling is critical to BMSCs’ pain-relieving effect, we further evaluated a role of chemokine signaling in p65 upregulation. Prior to infusion of BMSCs, we transduced BMSCs with Ccl4 shRNA, incubated BMSCs with RS 102895, a CCR2b antagonist, or maraviroc, a CCR5 antagonist. The antagonism of chemokines significantly reduced BMSC-induced upregulation of p65, suggesting that upregulation of p65 was related to BMSCs’ pain-relieving effect. We then tested the effect of a selective NF-κB activation inhibitor, BAY 11-7082. The mechanical hyperalgesia of the rat was assessed with the von Frey method. In the pre-treatment experiment, BAY 11-7082 (2.5 and 25 pmol) was injected into the RVM at 2 h prior to BMSC infusion. Pretreatment with BAY 11-7082 attenuated BMSCs’ antihyperalgesia, but post-treatment at 5 weeks post-BMSC was not effective. On the contrary, in TL rats receiving BAY 11-7082 without BMSCs, TL-induced hyperalgesia was attenuated, consistent with dual roles of NF-κB in pain hypersensitivity and BMSC-produced pain relief. These results indicate that the NF-κB signaling pathway in the descending circuitry is involved in initiation of BMSC-produced behavioral antihyperalgesia.

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“…They also showed that the levels of NFκB were elevated in the muscles of CPIP rats compared to sham rats 2 and 48 h after I/R injury. Ross-Huot et al [ 24 ] also demonstrated that the levels of NFκB in the ipsilateral hind paw muscles were higher in the relatively hyperglycemic groups 2 days post-I/R injury. Accordingly, the administration of SN50, a cell-permeable synthetic peptide which inhibits the translocation of the active NFκB complex into the nucleus [ 25 , 26 ], resulted in the reduction of mechanical allodynia.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Super-Repressor IkB-Loaded Exosomes (Exo-srIκBs) in Chronic Post-Ischemia Pain (CPIP) Models

Chae

Park

Ahn³

et al. 2023

Pharmaceutics

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Complex regional pain syndrome (CRPS) is a condition associated with neuropathic pain that causes significant impairment of daily activities and functioning. Nuclear factor kappa B (NFκB) is thought to play an important role in the mechanism of CRPS. Recently, exosomes loaded with super-repressor inhibitory kappa B (Exo-srIκB, IκB; inhibitor of NFκB) have been shown to have potential anti-inflammatory effects in various inflammatory disease models. We investigated the therapeutic effect of Exo-srIκB on a rodent model with chronic post-ischemia pain (CPIP), a representative animal model of Type I CRPS. After intraperitoneal injection of a vehicle, Exo-srIκB, and pregabalin, the paw withdrawal threshold (PWT) was evaluated up to 48 h. Administration of Exo-srIκB increased PWT compared to the vehicle and pregabalin, and the relative densities of p-IκB and IκB showed significant changes compared to the vehicle 24 h after Exo-srIκB injection. The levels of several cytokines and chemokines were reduced by the administration of Exo-srIκB in mice with CPIP. In conclusion, our results showed more specifically the role of NFκB in the pathogenesis of CRPS and provided a theoretical background for novel treatment options for CRPS.

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Glycemia-dependent Nuclear Factor κB Activation Contributes to Mechanical Allodynia in Rats with Chronic Postischemia Pain

Abstract: Background-Ischemia-reperfusion injury causes chronic postischemia pain (CPIP), and rats with higher glycemia during ischemia-reperfusion injury exhibit increased allodynia. Glycemiainduced elevation of nuclear factor kappa-B (NFκB) may contribute to increased allodynia.

Cited by 7 publications

References 37 publications

Upregulation of CX3CL1 mediated by NF-κB activation in dorsal root ganglion contributes to peripheral sensitization and chronic pain induced by oxaliplatin administration

Upregulation of CX3CL1 mediated by NF-κB activation in dorsal root ganglion contributes to peripheral sensitization and chronic pain induced by oxaliplatin administration

NF-KappaB Pathway Is Involved in Bone Marrow Stromal Cell-Produced Pain Relief

The Effect of Super-Repressor IkB-Loaded Exosomes (Exo-srIκBs) in Chronic Post-Ischemia Pain (CPIP) Models

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