Formaldehyde and Cancer Pain Figure 2. TRPV1 antagonists and formaldehyde scavengers inhibited formalin-induced pain response in rats. (A) Capsazepine (CPZ, a TRPV1 antagonist); (B) Melatonin (MT); (C and D) Formaldehyde scavengers: Resveratrol (Res) and Glutathione (GSH). mg/paw. * p,0.05, ** p,0.01, compared with the formaldehyde injection groups. n = 10. doi:10.1371/journal.pone.0010234.g002 study gives direct evidence that formaldehyde can be secreted from the cultured cancer cell lines in vitro and tumor tissues from certain cancer pain patients in vivo, and its concentration may reach abnormally high levels (Fig. 1). Because the bone cavity volume of rats is small and the amount of bone marrow tissue is little, four bone marrows from MRMT-1 breast cancer pain models were combined to one tube for HPLC measurement in the present study. A marked elevation of formaldehyde level was found in bone marrow of cancer pain model rats (Fig. 1E). This agrees with a previous report that formaldehyde could be accumulated in bone marrow [34]. Interestingly, formaldehyde level in blood was also obviously elevated in MRMT cancer pain model in rats (Fig. S1, B) and formaldehyde is considered as a cause of cancer [35]. These reports suggest that excessive formaldehyde production by tumor tissues is possibly a critical factor in tissue cancerization or osseous metastasis. Cancer tissue-derived excessive formaldehyde induces bone destruction Cancer cell metastasis to bone marrow increases osteolysis, osteoclastic activity and induces an acidic microenvironment [36]. This is related to the fact that osteoclasts resorb bone by maintaining an extracellular microenvironment of pH 4,5 [12]. Acidification is a cause of pain in cancer and inflammation [36]. The activated osteoclasts increase proton-induced stimulation of TRPV1 or acid-sensitive ion channels (ASICs) on sensory nerve PLoS ONE | www.plosone.org 5 April 2010 | Volume 5 | Issue 4 | e10234