Complete Freund's adjuvant-induced protein dysregulation correlated with mirror image pain as assessed by quantitative proteomics of the mouse spinal cord

Vesicular glutamate transporter type 2 (VGLUT2) is known to play an important role in mediating heat hyperalgesia induced by inflammation. However, the underlying mechanism for this activity is poorly understood. Cyclin-dependent kinase 5 (Cdk5), serving as a key regulator in modulating release of glutamate, acted a key player in the formation of heat hyperalgesia of inflammatory pain. However, it remains unknown whether there is a bridge between Cdk5 and VGLUT2 for mediating inflammatory pain. Therefore, we designed the experiment to determine whether VGLUT2 signaling pathway is involved in inflammatory pain mediated by Cdk5 in the inflammatory pain model induced by complete Freund’s adjuvant (CFA). Our results showed that the coexpression of Cdk5/VGLUT2 in small- and medium-sized neuronal cells of the dorsal root ganglion (DRG) and spinal cord between days 1 and 3 following subcutaneous injection of CFA was significantly increased. Moreover, our study revealed that the expression of VGLUT2 protein in the DRG and spinal cord was remarkably increased between days 1 and 3 following CFA injection and was significantly reduced by roscovitine, a selective antagonist of Cdk5. Additionally, p25 but not p35, an activator of Cdk5, protein was significantly increased by CFA and reduced by roscovitine. Our findings suggested that VGLUT2/Cdk5 signaling pathway contributes to inflammatory pain mediated by Cdk5/p25.

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Thymosin Alpha-1 Inhibits Complete Freund’s Adjuvant-Induced Pain and Production of Microglia-Mediated Pro-inflammatory Cytokines in Spinal Cord

Neuroscience Bulletin ◽

10.1007/s12264-019-00346-z ◽

2019 ◽

Vol 35 (4) ◽

pp. 637-648 ◽

Cited By ~ 3

Author(s):

Yunlong Xu ◽

Yanjun Jiang ◽

Lin Wang ◽

Jiahua Huang ◽

Junmao Wen ◽

...

Keyword(s):

Spinal Cord ◽

Inflammatory Cytokines ◽

Complete Freund’S Adjuvant ◽

Thymosin Alpha 1 ◽

Freund’S Adjuvant ◽

Complete Freund's Adjuvant ◽

Freund's Adjuvant ◽

Pro Inflammatory Cytokines

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Direct Evidence for the Ongoing Brain Activation by Enhanced Dynorphinergic System in the Spinal Cord under Inflammatory Noxious Stimuli

Anesthesiology ◽

10.1097/aln.0b013e3181ca31d9 ◽

2010 ◽

Vol 112 (2) ◽

pp. 418-431 ◽

Cited By ~ 6

Author(s):

Yasuko Taketa ◽

Keiichi Niikura ◽

Yasuhisa Kobayashi ◽

Masaharu Furuya ◽

Toshikazu Shimizu ◽

...

Keyword(s):

Spinal Cord ◽

Messenger Rna ◽

Intrathecal Injection ◽

Complete Freund’S Adjuvant ◽

Dynorphin A ◽

Intraplantar Injection ◽

Freund’S Adjuvant ◽

Complete Freund's Adjuvant ◽

Freund's Adjuvant ◽

Noxious Stimuli

Background Dynorphin A in the spinal cord is considered to contribute to nociceptive stimuli. However, it has not yet been determined whether activation of the spinal dynorphinergic system under nociceptive stimuli plays a role in direct acceleration of the ascending nociceptive pathway. In this study, the authors investigated the role of spinal dynorphinergic transmission in ongoing brain activation under noxious stimuli in mice. Methods The changes in prodynorphin messenger RNA expression and dynorphin A (1-17)-like immunoreactivity in the mouse spinal cord were determined after the intraplantar injection of complete Freund's adjuvant in mice. The signal intensity in different brain regions after the intraplantar injection of complete Freund's adjuvant or intrathecal injection of dynorphin A (1-17) was measured by a pharmacological functional magnetic resonance imaging analysis. Results Complete Freund's adjuvant injection produced pain-associated behaviors and induced a dramatic increase in signal intensity in the mouse cingulate cortex, somatosensory cortex, insular cortex, and thalamic nuclei. These effects were not seen in prodynorphin knockout mice. Prodynorphin messenger RNA expression and dynorphin A (1-17)-like immunoreactivity on the ipsilateral side of the spinal cord were markedly increased in complete Freund's adjuvant-injected mice. Furthermore, intrathecal injection of dynorphin A (1-17) at relatively high doses caused pain-associated behaviors and a remarkable increase in the activities of the cingulate cortex, somatosensory cortex, insular cortex, and medial and lateral thalamic nuclei in mice. Conclusions These findings indicate that spinally released dynorphin A (1-17) by noxious stimuli leads to the direct activation of ascending pain transmission.

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Role of Spinal Cord Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors in Complete Freund's Adjuvant-Induced Inflammatory Pain

Molecular Pain ◽

10.1186/1744-8069-4-67 ◽

2008 ◽

Vol 4 ◽

pp. 1744-8069-4-67 ◽

Cited By ~ 46

Author(s):

Jang-Su Park ◽

Myron Yaster ◽

Xiaowei Guan ◽

Ji-Tian Xu ◽

Ming-Hung Shih ◽

...

Keyword(s):

Spinal Cord ◽

Inflammatory Pain ◽

Complete Freund’S Adjuvant ◽

Freund’S Adjuvant ◽

Complete Freund's Adjuvant ◽

Freund's Adjuvant

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Trifluoro-Icaritin Ameliorates Complete Freund’s Adjuvant-Induced Inflammatory Pain by α7nAChR-Mediated Inhibition of HMGB1/NF-κB Signaling in the Spinal Cord of Rats

10.21203/rs.3.rs-572585/v1 ◽

2021 ◽

Author(s):

Yalan Sun ◽

Dandan Jia ◽

Meng Xue ◽

Guangsen Liu ◽

Zhihua Huang ◽

...

Keyword(s):

Spinal Cord ◽

Inflammatory Pain ◽

Intrathecal Injection ◽

Complete Freund’S Adjuvant ◽

Immunofluorescence Staining ◽

Western Blot Assay ◽

Freund’S Adjuvant ◽

Complete Freund's Adjuvant ◽

Freund's Adjuvant ◽

Alpha Bungarotoxin

Abstract Objectives: To explore whether Trifluoro-icaritin (ICTF) has anti-nociceptive effect on CFA-induced inflammatory pain and its potential mechanisms. Methods: Intraperitoneal injection (0.3, 1.0, and 3.0 mg/kg, i.p.) of ICTF to complete Freund’s adjuvant (CFA)-induced inflammatory pain rats once daily for 21 consecutive days. Pain-related behaviors were evaluated with paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and CatWalk gait analysis. Hematoxylin eosin (HE) staining was applied to determine the morphological alterations in inflamed paw. Molecular docking was conducted to assess the possible targets for ICTF. Expression of pain-related signaling molecules in the spinal cord were detected using qRT-PCR, western blot assay, and immunoﬂuorescence staining. Results:This results showed that ICTF(3.0 mg/kg) effectively alleviated mechanical allodynia and thermal hyperalgesiabut not 0.3 and 1.0 mg/kg in CFA rats. Both paw edema volume and paw tissue inflammatory response were obviously reduced by ICTF. Subsequently, we further observed that ICTF dramatically decreased the mRNA and protein levels of HMGB1, NF-κB p65, and IL-1β but markedly enhanced α7nAChR and IL-10 expression in the spinal cord of CFA rats, and inhibitedthe co-expression of spinal α7nAChR with IBA-1 in double immunofluorescence staining,along with suppressing the alterations of gait parameters induced by CFA. Moreover, Intrathecal injection (i.t.) of α7nAChR antagonist alpha-bungarotoxin (α-Bgtx, 1.0 μg/kg) not only reversed the anti-nociceptive effect of ICTF on pain hypersensitivity, but also inhibited the down-regulation of HMGB1, NF-κB p65, and IL-1β as well as the up-regulation of α7nAChR and IL-10 protein expression induced by ICTF treatment.Conclusion: Our results illustrate that ICTF enables to alleviate CFA-induced inflammatory pain through α7nAChR-mediated inhibition of HMGB1/NF-κB signaling pathway in the spinal cord of rats, suggesting that ICTF may be exploited as a potential painkiller against chronic inflammatory pain.

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