Activation of spinal neuregulin 1-ErbB2 signaling pathway in a rat model of cancer-induced bone pain.

Abstract

Current therapies for cancer-induced bone pain (CIBP) are still limited. Until recently, the molecular mechanisms underlying the spinal cell-mediated CIBP remain largely unknown. To better understand the role of spinal cells in CIBP, we investigated the role of spinal neuregulin1 (NRG1)‑ErbB2 signaling pathway in CIBP. In this study, a rat model of CIBP was established by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Tibia bone destruction was evaluated using various methods of Walker 256 inoculation, radiobioassay and histological analysis. Pain-like behavior including thermal hyperalgesia and mechanical allodynia were determined by measuring paw withdrawal latency (PWL) and mechanical paw withdrawal thresholds (PWT). The expression level of mRNA or protein of target genes was examined by quantitative reverse transcription-polymerase chain reaction (qPCR) and western blot analysis, respectively. Bone destruction, as well as thermal hyperalgesia and mechanical allodynia, were observed at the 6th day following Walker 256 inoculation. A time-dependent increase in the levels of NRG1, ErbB2 and p-ErbB2 could be detected within three weeks after tumor cell injection. ErbB2 signaling inactivation by PD168393 treatment significantly attenuated pain-like behavior, associated with inhibition of Akt-1 and p38MAPK activation. Administration of exogenous NRG1 provoked pain-like behavior in rats by induction of activation of ErbB2, Akt-1 and p38MAPK, which could be blocked by ErbB2 inhibitor. Our results indicate that activation of NRG1‑ErbB2 signaling pathway plays a critical role in the induction of CIBP. Akt-1 and p38MAPK may be potent players involved in the NRG1-ErbB2 pathway in CIBP.