Participation of pro-inflammatory cytokines in neuropathic pain evoked by chemotherapeutic oxaliplatin via central GABAergic pathway

Xu, Dongsheng; Zhao, Hui; Gao, Han; Zhao, Huiling; Liu, Dandan; Li, Jing

doi:10.1177/1744806918783535

Cited by 40 publications

(25 citation statements)

References 43 publications

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“…As PI3K or mTOR signal was inhibited, mechanical and cold hypersensitivity were attenuated in oxaliplatin treated rats, and the levels of proinflammatory cytokines also decreased [38]. The upregulation of pro-inflammatory cytokines and membrane pro-inflammatory cytokine receptors in the midbrain periaqueductal gray, which has an inhibitory or excitatory control on pain transmission via the rostral ventromedial medulla, projecting to the spinal dorsal horn, of oxaliplatin treated rats is likely to impair the descending inhibitory pathways in regulation of pain transmission and thereby, contribute to the development of neuropathic pain after the administration of chemotherapeutic oxaliplatin [39]. These reports suggest that the mechanism of development of oxaliplatin-induced neuropathy resembles inflammatory pain.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain

et al. 2019

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Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 μg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.

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Section: Discussionmentioning

confidence: 99%

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain

et al. 2019

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“…Interestingly, supraspinal mechanisms such as activation of cortical areas important in pain processing, and descending facilitation from key brainstem areas may contribute in contralateral allodynia as well [97,98] . Proinflammatory cytokines in pain related brain regions are capable of impairing descending inhibitory pain pathways [99] . Whether, differential immune mechanisms following nerve injury influence the descending pathways involved in manifesting mirror image pain in different sexes would be an interesting avenue for future exploration.…”

Section: Sex Convergent and Sex Divergent Aberrant Spinal Immune Respmentioning

confidence: 99%

LFA-1 antagonist (BIRT377) similarly reverses peripheral neuropathic pain in male and female mice with underlying sex divergent peripheral immune proinflammatory phenotypes

Noor¹,

Sun²,

Vanderwall³

et al. 2019

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Aim: The majority of preclinical studies investigating aberrant glial-neuroimmune actions underlying neuropathic pain have focused on male rodent models. Recently, studies have shown peripheral immune cells play a more prominent role than glial cells in mediating pathological pain in females. Here, we compared the onset and duration of allodynia in males and females, and the anti-allodynic action of a potentially novel therapeutic drug (BIRT377) that not only antagonizes the action of lymphocyte function-associated antigen-1 (LFA-1) to reduce cell migration in the periphery, but may also directly alter the cellular inflammatory bias. Methods: Male and female mice were subjected to peripheral nerve injury chronic constriction injury (CCI) applying two methods, using either 4-0 or 5-0 chromic gut suture material, to examine potential sex differences in the onset, magnitude and duration of allodynia. Hindpaw sensitivity before and after CCI and application of intravenous BIRT377 was assessed. Peripheral and spinal tissues were analyzed for protein (multiplex electrochemiluminescence technology) and mRNA expression (quantitative real-time PCR). The phenotype of peripheral T cells was determined using flow cytometry. Results: Sex differences in proinflammatory CCL2 and IL-1β and the anti-inflammatory IL-10 were observed from a set of cytokines analyzed. A profound proinflammatory T cell (Th17) response in the periphery and spinal cord was also observed in neuropathic females. BIRT377 reversed pain, reduced IL-1β and TNF, and increased IL-10 and transforming growth factor (TGF)-β1, also an anti-inflammatory cytokine, in both sexes. However, female-derived T cell cytokines are transcriptionally regulated by BIRT377, as demonstrated by reducing proinflammatory IL-17A production with concurrent increases in IL-10, TGF-β1 and the anti-inflammatory regulatory T cell-related factor, FOXP3. Conclusion: This study supports that divergent peripheral immune and neuroimmune responses during neuropathy exists between males and females. Moreover, the modulatory actions of BIRT377 on T cells during neuropathy are predominantly specific to females. These data highlight the necessity of including both sexes for studying drug efficacy and mechanisms of action in preclinical studies and clinical trials.

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“…[49] Elevated TNF-α levels appear to correlate to high pain scores in thoracic disc herniations,[50] and it is thought that TNF-α is one of the pro-inflammatory cytokines involved in neuropathic pain through a GABAergic mechanism. [51] Immune cells are recruited in response to injury and could induct the sensitization of peripheral nociceptors, thus beginning a complex interactive network of inflammatory mediators, neurotransmitters, immune cells, neurons/support cells that synchronizes immune responses, and pain pathway modulation. [52] The beneficial effects of long-term yoga on stress responses, especially C-reactive protein and serum IL-6 levels,[53] highlights the potential benefits of yoga on the immune system.…”

Section: Discussionmentioning

confidence: 99%

Physical and physiological effects of yoga for an underserved population with chronic low back pain

et al. 2019

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Background:Yoga has been shown useful in reducing chronic low back pain (CLBP) through largely unknown mechanisms. The aim of this pilot study is to investigate the feasibility of providing yoga intervention to a predominantly underserved population and explore the potential mechanisms underlying yoga intervention in improving CLBP pain.Methods:The quasi-experimental within-subject wait-listed crossover design targeted the recruitment of low-income participants who received twice-weekly group yoga for 12 weeks, following 6–12 weeks of no intervention. Outcome measures were taken at baseline, preintervention (6–12 weeks following baseline), and then postintervention. Outcome measures included pain, disability, core strength, flexibility, and plasma tumor necrosis factor (TNF)-α protein levels. Outcomes measures were analyzed by one-way ANOVA and paired one-tailed t-tests.Results:Eight patients completed the intervention. Significant improvements in pain scores measured over time were supported by the significant improvement in pre- and post-yoga session pain scores. Significant improvements were also seen in the Oswestry Disability Questionnaire scores, spinal and hip flexor flexibility, and strength of core muscles following yoga. Six participants saw a 28.6%–100% reduction of TNF-α plasma protein levels after yoga, while one showed an 82.4% increase. Two participants had no detectable levels to begin with. Brain imaging analysis shows interesting increases in N-acetylaspartate in the dorsolateral prefrontal cortex and thalamus.Conclusion:Yoga appears effective in reducing pain and disability in a low-income CLBP population and in part works by increasing flexibility and core strength. Changes in TNF-α protein levels should be further investigated for its influence on pain pathways.

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Participation of pro-inflammatory cytokines in neuropathic pain evoked by chemotherapeutic oxaliplatin via central GABAergic pathway

Cited by 40 publications

References 43 publications

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain

LFA-1 antagonist (BIRT377) similarly reverses peripheral neuropathic pain in male and female mice with underlying sex divergent peripheral immune proinflammatory phenotypes

Physical and physiological effects of yoga for an underserved population with chronic low back pain

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