Formaldehyde and Cancer Pain Figure 3. Capsaicin- or formaldehyde (100 ml/paw)-induced acute pain responses. (A) Melatonin, capsazepine and AP-18 attenuated formaldehyde-induced pain responses. (B) Low pH enhanced formaldehyde-induced pain responses. (C) Melatonin (MT) and capsazepine (CPZ) blocked capsaicin (0.5 mM)-induced pain responses. (D) AP-18 did not block capsaicin-induced pain responses. Con: control; DMSO: vehicle; CAP: capsaicine. * p,0.05, ** p,0.01, ## p,0.01, & p,0.05, && p,0.01, all compared with respective controls. n = 10. doi:10.1371/journal.pone.0010234.g003 fibers that innervate bone [1]. Another source of protons is lysis of tumor cells themselves. Cancer cells have a lower intracellular pH than normal cells [37], as solid tumors outgrow their vascular supply, then cancer tissue becomes necrotic, which contributes to the acidic environment [38]. A recent research report also demonstrated that formaldehyde, gradually released by root canal sealers, elicited bone necrosis [39]. Elevated formaldehyde was also observed in patients with dental caries [40]. Cytotoxicity resulting from excessive formaldehyde on human osteoblastic cells has been considered to be an important factor in bone destruction [41,42]. Formaldehyde can accumulate in bone marrow [34]. In our present study, formaldehyde concentration was elevated to about 0.6 mM in bone marrow of MRMT-1 bone cancer pain model in rats (Fig. 1E). This level is high enough to be toxic to osteoblastic cells. Bone destruction was found in the MRMT-1 bone cancer pain model in rats. Formaldehyde scavengers, resveratrol and glutathione obviously decreased bone destruction in the present study (Figs. 6B, 7A and 7B). Therefore, excessive formaldehyde secreted by cancer tissues may play a role in bone destruction. This bone destruction then contributes to cancer pain, because nerve fiber endings innervating bone is more easily exposed to tumor tissue-derived factors. Formaldehyde induces pain responses via TRPV1 and/or TRPA1 Breast, lung and bladder cancer patients frequently suffer from bone cancer pain [5,6]. In the present study, mechanical allodynia was found in breast cancer pain patients and in the affected hind PLoS ONE | www.plosone.org 6 April 2010 | Volume 5 | Issue 4 | e10234