Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151825 (bone pain)
 3,118 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been reported that Toll-like receptor 4 (TLR4), which plays an important role in glial activation in neuropathic pain, is significantly increased in cancer pain. The present study was designed to assess the role of TLR4 in cancer-induced bone pain (CIBP) by intrathecal administration of TLR4 signaling pathway blocker naloxone or lipopolysaccharide Rhodobacter sphaeroides (LPS-RS). The rats developed significant mechanical allodynia from day 8 after intratibial Walker 256 inoculation. Intrathecal injection of naloxone or LPS-RS at day 8 significantly attenuated mechanical allodynia as shown by increased paw withdrawal thresholds. In contrast, the same pharmacological treatment showed no or slight pain relieving effect at day 16. Our findings demonstrate that the spinal TLR4 signaling pathway contributes to the mechanism underlying CIBP in a stage-dependent manner in rats, and it may be an efficacious target at early stage for the treatment in the future.
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PMID:Stage-dependent anti-allodynic effects of intrathecal Toll-like receptor 4 antagonists in a rat model of cancer induced bone pain. 2339 1

Bone pain is a common complication of breast cancer (BC) bone metastasis and is a major cause of increased morbidity and mortality. Although the mechanism of BC-associated bone pain (BCABP) remains poorly understood, involvement of BC products in the pathophysiology of BCABP has been proposed. Aggressive cancers secrete damage-associated molecular patterns (DAMPs) that bind to specific DAMP receptors and modulate cancer microenvironment. A prototypic DAMP, high mobility group box 1 (HMGB1), which acts as a ligand for the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), is increased in its expression in BC patients with poor outcomes. Here we show that 4T1 mouse BC cells colonizing bone up-regulate the expression of molecular pain markers, phosphorylated ERK1/2 (pERK) and pCREB, in the dorsal root ganglia (DRGs) innervating bone and induced BCABP as evaluated by hind-paw mechanical hypersensitivity. Importantly, silencing HMGB1 in 4T1 BC cells by shRNA reduced pERK and pCREB and BCABP with decreased HMGB1 levels in bone. Further, administration of a neutralizing antibody to HMGB1 or an antagonist for RAGE, FPS-ZM1, ameliorated pERK, pCREB and BCABP, while a TLR4 antagonist, TAK242, showed no effects. Consistent with these in vivo results, co-cultures of F11 sensory neuron-like cells with 4T1 BC cells in microfluidic culture platforms increased neurite outgrowth of F11 cells, which was blocked by HMGB1 antibody. Our results show that HMGB1 secreted by BC cells induces BCABP via binding to RAGE of sensory neurons and suggest that the HMGB1/RAGE axis may be a potential novel therapeutic target for BCABP.
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PMID:The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone. 3320 6