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. 2012 Feb 29;28(2):165–172. doi: 10.1007/s12264-012-1211-0

Formaldehyde up-regulates TRPV1 through MAPK and PI3K signaling pathways in a rat model of bone cancer pain

Ying Han 1, Yan Li 1, Xing Xiao 1, Jia Liu 1, Xiang-Ling Meng 1, Feng-Yu Liu 1, Guo-Gang Xing 1, You Wan 1,2,3,✉
PMCID: PMC5560397  PMID: 22466127

Abstract

Objective

Our previous study showed that tumor tissue-derived formaldehyde at low concentrations plays an important role in bone cancer pain through activating transient receptor potential vanilloid subfamily member 1 (TRPV1). The present study further explored whether this tumor tissue-derived endogenous formaldehyde regulates TRPV1 expression in a rat model of bone cancer pain, and if so, what the possible signal pathways are during the development of this type of pain.

Methods

A rat model of bone cancer pain was established by injecting living MRMT-1 tumor cells into the tibia. The formaldehyde levels were determined by high performance liquid chromatography, and the expression of TRPV1 was examined with Western blot and RT-PCR. In primary cultured dorsal root ganglion (DRG) neurons, the expression of TRPV1 was assessed after treatment with 100 μmol/L formaldehyde with or without pre-addition of PD98059 [an inhibitor for extracellular signal-regulated kinase], SB203580 (a p38 inhibitor), SP600125 [an inhibitor for c-Jun N-terminal kinase], BIM [a protein kinase C (PKC) inhibitor] or LY294002 [a phosphatidylinositol 3-kinase (PI3K) inhibitor].

Results

In the rat model of bone cancer pain, formaldehyde concentration increased in blood plasma, bone marrow and the spinal cord. TRPV1 protein expression was also increased in the DRG. In primary cultured DRG neurons, 100 μmol/L formaldehyde significantly increased the TRPV1 expression level. Pre-incubation with PD98059, SB203580, SP600125 or LY294002, but not BIM, inhibited the formaldehyde-induced increase of TRPV1 expression.

Conclusion

Formaldehyde at a very low concentration up-regulates TRPV1 expression through mitogen-activated protein kinase and PI3K, but not PKC, signaling pathways. These results further support our previous finding that TRPV1 in peripheral afferents plays a role in bone cancer pain.

Keywords: formaldehyde, TRPV1, cancer pain, mitogen-activated protein kinase, phosphatidylinositol 3-kinase

Footnotes

These authors contributed equally to this work.

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