minocycline and Musculoskeletal-Pain

Cancer-induced bone pain (CIBP) is a common clinical problem in breast cancer patients with bone metastasis. Recent studies shows chemokines are novel targets for treatment of CIBP. In this study, we intra-tibial inoculated with Walker 256 rat mammary gland carcinoma cells into rat bone to established metastatic breast cancer. Then we measured the expression of CXCL10 in the spinal cord of metastatic bone cancer rats, investigated the role of CXCL10 in the development of CIBP, and the underlying mechanism. Results revealed that after intra-tibial inoculation with Walker 256 cells, rats showed up-regulation of CXCL10 and its receptor CXCR3 in the spinal cord. Interestingly, intrathecally injection of recombinant CXCL10 protein induced mechanical allodynia in naïve rats. Blocking the function of CXCL10/CXCR3 pathway via anti-CXCL10 antibody or CXCR3 antagonist prevented the development of CIBP and microglial activation. Moreover, CXCL10-induced mechanical allodynia was rescued by minocycline treatment during the late-stage of CIBP, days 10-14. The regulation of CXCL10 expression involved microglial activation in a manner of autocrine positive feedback. These results suggest that CXCL10 may be a necessary algogenic molecule, especially in the development of CIBP. Its function was partly mediated via spinal microglial activation. This study provides a novel insight into the biological function of chemokine CXCL10 in the molecular mechanism underlying cancer pain. It also provides new target for clinical treatment of metastatic breast cancer-induced bone pain in future.

Topics: Animals; Anti-Bacterial Agents; Bone Neoplasms; Carcinoma 256, Walker; Chemokine CXCL10; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Hyperalgesia; Interferon-gamma; Mammary Neoplasms, Experimental; Microglia; Minocycline; Musculoskeletal Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, CXCR3; Spinal Cord

The rodent acidic saline model of hyperalgesia uses repeat injections of acidic saline in the right lateral gastrocnemius muscle, spaced five days apart, to induce a persistent decrease in hindpaw withdrawal thresholds. The objective of this study was to determine if alternate injection sites would permit development of hyperalgesia.. The location of the first muscle injection was varied between 3 groups of rats to include the right lateral gastrocnemius, the right medial gastrocnemius or the left lateral gastrocnemius. All second injections were placed in the right lateral gastrocnemius.. As reported by others, placing both injections in the right lateral gastrocnemius produced a significant reduction in paw withdrawal thresholds 24 hours after the second injection (p < 0.05). Relocating the first injection to the right medial gastrocnemius or the left lateral gastrocnemius also produced significant reductions in paw withdrawal thresholds (p < 0.05 for both). Hyperalgesia was also observed if the first muscle injection was replaced with a systemic injection of lipopolysaccharide. Further experiments tested whether glia cells may contribute to the priming process. Pretreatment with minocycline prior to the first injection completely blocked the development of hyperalgesia but was ineffective if injected before the second injection.. These data indicate that anatomically diverse peripheral stimuli can converge within the central nervous system to produce hyperalgesia.

Topics: Acids; Animals; Disease Models, Animal; Hyperalgesia; Minocycline; Muscle, Skeletal; Musculoskeletal Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Sodium Chloride