Enhanced binding capability of nuclear factor-κB with demethylated P2X3 receptor gene contributes to cancer pain in rats

Zhou, Youlang; Jiang, Guoqin; Wei, Jinrong; Zhang, Honghong; Chen, Wei; Zhu, Hongyan; Hu, Shu‐Fen; Jiang, Xinghong; Xu, Guang–Yin

doi:10.1097/j.pain.0000000000000248

Cited by 56 publications

(52 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present study confirms previous results obtained in the mouse [19; 20; 25; 34], rat [31; 40; 67; 73], and human [58] that bone cancer pain can induce a hypersensitivity of the nearby skin. Currently, the mechanism(s) by which skeletal pain drives skin hypersensitivity are not well understood.…”

Section: Discussionsupporting

confidence: 92%

“…Both therapies, anti-P2X3 and anti-NGF, are mouse monoclonal antibodies that do not readily cross the blood brain barrier (BBB) and thus most likely exert their effects outside the BBB [49]. It should also be noted that previous studies [22; 31; 39; 67; 73] examining whether P2X3 antagonists can relieve bone cancer pain and/or bone cancer pain induced skin hypersensitivity all employed small molecule P2X3 antagonists which unlike, anti-P2X3 or anti-NGF, probably readily cross the BBB.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

Guedon

Longo

Majuta

et al. 2016

Pain

View full text Add to dashboard Cite

Recent studies have suggested that in humans and animals with significant skeletal pain, changes in the mechanical hypersensitivity of the skin can be detected. However, whether measuring changes in skin hypersensitivity can be a reliable surrogate for measuring skeletal pain itself remains unclear. To explore this question we generated skeletal pain by injecting and confining GFP-transfected NCTC 2472 osteosarcoma cells unilaterally to the femur of C3H male mice. Beginning at day 7 post-tumor injection, animals were administered vehicle, an antibody to the P2X3 receptor (anti-P2X3) or anti-NGF antibody. Pain and analgesic efficacy was then measured on days 21, 28 and 35 post-tumor injection using a battery of skeletal pain-related behaviors and von Frey assessment of mechanical hypersensitivity on the plantar surface of the hindpaw. Animals with bone cancer pain treated with anti-P2X3 showed a reduction in skin hypersensitivity but no attenuation of skeletal pain behaviors. Whereas animals with bone cancer pain treated with anti-NGF showed a reduction in both skin hypersensitivity and skeletal pain behaviors. These results suggest that while bone cancer can induce significant skeletal pain-related behaviors and hypersensitivity of the skin, relief of hypersensitivity of the skin is not always accompanied by attenuation of skeletal pain. Understanding the relationship between skeletal and skin pain may provide insight into how pain is processed and integrated and help define the preclinical measures of skeletal pain that are predictive endpoints for clinical trials.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

Guedon

Longo

Majuta

et al. 2016

Pain

View full text Add to dashboard Cite

show abstract

“…Epigenetic regulation can be carried out at a variety of levels, such as DNA methylation and histone modification, in which DNA methylation is particularly common. Several studies have suggested that epigenetic especially DNA methylation is involved in pain modulation . Recently, some studies have reported that complete Freund's adjuvant (CFA) injection significantly upregulates histone deacetylase HDACs expression, whereas administration of HDACs blockers significantly relieves CFA‐induced inflammatory pain .…”

Section: Introductionmentioning

confidence: 99%

Upregulation of CXCR4 through promoter demethylation contributes to inflammatory hyperalgesia in rats

Xue

Yuan

et al. 2018

CNS Neurosci Ther

View full text Add to dashboard Cite

show abstract

“…In support of this possibility, there are several recent reports indicating that particular histone post‐translational modifications, as well as changes in DNA methylation and DNA hydroxymethylation, contribute to modulate the expression of genes associated with pain sensation . Moreover, a recently published work demonstrates that in rat tumor cells hypomethylation of the P2X3‐R gene promoter sequences facilitates binding of components of the NF‐κB family of transcriptional regulators and promotes pain sensitivity …”

Section: Discussionmentioning

confidence: 92%

Variable transcriptional responsiveness of the P2X3 receptor gene during CFA‐induced inflammatory hyperalgesia

Nunez-Badinez

Sepúlveda

Dı́az

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

The purinergic receptor P2X3 (P2X3‐R) plays important roles in molecular pathways of pain, and reduction of its activity or expression effectively reduces chronic inflammatory and neuropathic pain sensation. Inflammation, nerve injury, and cancer‐induced pain can increase P2X3‐R mRNA and/or protein levels in dorsal root ganglia (DRG). However, P2X3‐R expression is unaltered or even reduced in other pain studies. The reasons for these discrepancies are unknown and might depend on the applied traumatic intervention or on intrinsic factors such as age, gender, genetic background, and/or epigenetics. In this study, we sought to get insights into the molecular mechanisms responsible for inflammatory hyperalgesia by determining P2X3‐R expression in DRG neurons of juvenile male rats that received a Complete Freund's Adjuvant (CFA) bilateral paw injection. We demonstrate that all CFA‐treated rats showed inflammatory hyperalgesia, however, only a fraction (14‐20%) displayed increased P2X3‐R mRNA levels, reproducible across both sides. Immunostaining assays did not reveal significant increases in the percentage of P2X3‐positive neurons, indicating that increased P2X3‐R at DRG somas is not critical for inducing inflammatory hyperalgesia in CFA‐treated rats. Chromatin immunoprecipitation (ChIP) assays showed a correlated (R2 = 0.671) enrichment of the transcription factor Runx1 and the epigenetic active mark histone H3 acetylation (H3Ac) at the P2X3‐R gene promoter in a fraction of the CFA‐treated rats. These results suggest that animal‐specific increases in P2X3‐R mRNA levels are likely associated with the genetic/epigenetic context of the P2X3‐R locus that controls P2X3‐R gene transcription by recruiting Runx1 and epigenetic co‐regulators that mediate histone acetylation.

show abstract

Enhanced binding capability of nuclear factor-κB with demethylated P2X3 receptor gene contributes to cancer pain in rats

Abstract: Supplemental Digital Content is Available in the Text.Epigenetic regulations of P2X3 receptors play a crucial role in cancer pain. Targeting p65 binding to demethylated P2X3 receptor gene suppresses cancer pain.

Cited by 56 publications

References 46 publications

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

Upregulation of CXCR4 through promoter demethylation contributes to inflammatory hyperalgesia in rats

Variable transcriptional responsiveness of the P2X3 receptor gene during CFA‐induced inflammatory hyperalgesia

Contact Info

Product

Resources

About