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Bone pain is one of the most common complications in cancer patients with bone metastases. Previous findings that inhibitors of osteoclastic bone resorption such as bisphosphonates (BPs) reduce bone pain suggest a critical role of osteoclasts. Osteoclasts destroy bone by secreting protons, thereby making adjacent microenvironment acidic. Because acidosis is a well-known cause of pain, it is plausible that an osteoclasts-created acidic microenvironment may cause bone pain associated with cancer colonization in bone. To test this notion, we studied an animal model in which inoculation of MRMT-1 rat breast cancer cells into the tibiae in female rats induced hyperalgesia. Radiographic and histological analyses demonstrated that MRMT-1 cells caused aggressive bone destruction with an increased number of osteoclasts. Behavioral analyses showed that rats exhibited hyperalgesia in the tumor-inoculated legs. The BP zoledronic acid (ZOL) significantly reduced the hyperalgesia. In addition, immunohistochemical examinations revealed that c-Fos expression in the ipsilateral spinal cord neurons was increased. ZOL decreased these c-Fos-positive neurons. To investigate the role of acidosis, mRNA expression of acid-sensing receptors including acid-sensing channels (ASICs) and transient receptor potential channel-vanilloid subfamily member 1 (TRPV1) in the dorsal root ganglions (DRGs) was determined. The expression of ASIC1a and ASIC1b was increased in the ipsilateral DRGs, whereas the ASIC3 and TRPV1 expression was not changed. Of note, ZOL reduced the expression of ASIC1a and ASIC1b. In conclusion, our data suggest that an acidic microenvironment created by osteoclasts, at least in part, contributes to the induction of hyperalgesia through upregulating ASICs expression.

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