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Pain is the most common symptom of bone cancer. TGF-ß, a major bone-derived growth factor, is largely released by osteoclast bone resorption during the progression of bone cancer and contributes to proliferation, angiogenesis, immunosuppression, invasion, and metastasis. Here, we further show that TGF-ß 1 is critical for bone cancer-induced pain sensitization. We found that, after the progression of bone cancer, TGF-ß1 was highly expressed in tumor-bearing bone, and the expression of its receptors, TGFßRI and TGFßRII, was significantly increased in the DRG in a rat model of bone cancer pain that is based on intratibia inoculation of Walker 256 mammary gland carcinoma cells. The blockade of TGF-ß receptors by the TGFßRI antagonist SD-208 robustly suppressed bone cancer-induced thermal hyperalgesia on post-tumor day 14 (PTD 14). Peripheral injection ofTGF-ß1 directly induced thermal hyperalgesia in intact rats and wide-type mice, but not in Trpvl-/- mice. Whole-cell patch-clamp recordings from DRG neurons showed that transient receptor potential vanilloid (TRPV1) sensitivity was significantly enhanced on PTD 14. Extracellular application ofTGF-ß1 significantly potentiated TRPV1 currents and increased [Ca2+]i in DRG neurons. Pharmacological studies revealed that the TGF-ß1 sensitization of TRPV1 and the induction of thermal hyperalgesia required the TGF-ßR-mediated Smad-independent PKCe and TGF-ß activating kinase 1-p38 pathways. These findings suggest that TGF-ß1 signaling contributes to bone cancer pain via the upregulation and sensitization of TRPV1 in primary sensory neurons and that therapeutic targeting ofTGF-ß1 may ameliorate the bone cancer pain in advanced cancer. [ABSTRACT FROM AUTHOR]

The anterior cingulate cortex (ACC) is implicated in the affective response to noxious stimuli. However, little is known about the molecular mechanisms involved. The present study demonstrated that extracellular signal-regulated kinase (ERK) activation in the ACC plays a crucial role in pain-related negative emotion. Intraplantar formalin injection produced a transient ERK activation in laminae V-VI and a persistent ERK activation in laminae II-III of the rostral ACC (rACC) bilaterally. Using formalin-induced conditioned place avoidance (F-CPA) in rats, which is believed to reflect the pain-related negative emotion, we found that blockade of ERK activation in the rACC with MEK inhibitors prevented the induction of F-CPA. Interestingly, this blockade did not affect formalin-induced two-phase spontaneous nociceptive responses and CPA acquisition induced by electric foot-shock or U69,593, an innocuous aversive agent. Upstream, NMDA receptor, adenylyl cyclase (AC) and phosphokinase A (PKA) activators activated ERK in rACC slices. Consistently, intra-rACC microinjection of AC or PKA inhibitors prevented F-CPA induction. Downstream, phosphorylation of cAMP response element binding protein (CREB) was induced in the rACC by formalin injection and by NMDA, AC and PKA activators in brain slices, which was suppressed by MEK inhibitors. Furthermore, ERK also contributed to the expression of pain-related negative emotion. Thus, when rats were re-exposed to the conditioning context for retrieval of pain experience, ERK and CREB were reactivated in the rACC, and inhibiting ERK activation blocked the expression of F-CPA. All together, our results demonstrate that ERK activation in the rACC is required for the induction and expression of pain-related negative affect. [ABSTRACT FROM AUTHOR]