BackgroundRapid and effective treatment of cancer-induced bone pain remains a clinical challenge and patients with bone metastasis are more likely to experience severe pain. The voltage-gated sodium channel Nav1.8 plays a critical role in many aspects of nociceptor function. Therefore, we characterized a rat model of cancer pain and investigated the potential role of Nav1.8.MethodsAdult female Wistar rats were used for the study. Cancer pain was induced by inoculation of Walker 256 breast carcinosarcoma cells into the tibia. After surgery, mechanical and thermal hyperalgesia and ambulation scores were evaluated to identify pain-related behavior. We used real-time RT-PCR to determine Nav1.8 mRNA expression in bilateral L4/L5 dorsal root ganglia (DRG) at 16-19 days after surgery. Western blotting and immunofluorescence were used to compare the expression and distribution of Nav1.8 in L4/L5 DRG between tumor-bearing and sham rats. Antisense oligodeoxynucleotides (ODNs) against Nav1.8 were administered intrathecally at 14-16 days after surgery to knock down Nav1.8 protein expression and changes in pain-related behavior were observed.ResultsTumor-bearing rats exhibited mechanical hyperalgesia and ambulatory-evoked pain from day 7 after inoculation of Walker 256 cells. In the advanced stage of cancer pain (days 16-19 after surgery), normalized Nav1.8 mRNA levels assessed by real-time RT-PCR were significantly lower in ipsilateral L4/L5 DRG of tumor-bearing rats compared with the sham group. Western-blot showed that the total expression of Nav1.8 protein significantly decreased bilaterally in DRG of tumor-bearing rats. Furthermore, as revealed by immunofluorescence, only the expression of Nav1.8 protein in small neurons down regulated significantly in bilateral DRG of cancer pain rats. After administration of antisense ODNs against Nav1.8, Nav1.8 protein expression decreased significantly and tumor-bearing rats showed alleviated mechanical hyperalgesia and ambulatory-evoked pain.ConclusionsThese findings suggest that Nav1.8 plays a role in the development and maintenance of bone cancer pain.

The climatological characteristics of water vapor transport over the Tibetan Plateau (TP) were investigated in this study by using the ERA-interim and JRA55 monthly reanalysis dataset. The trends of water vapor budget and water vapor sources during the past 40 years were also revealed. The analyses show that the TP is a water vapor convergence area, where the convergence was enhanced from 1979 to 2018. In addition, the convergence is much stronger in JJA, with a linear trend that is twice the annual average trend. The climatological water vapor sources over the TP were identified mainly at the southern and western boundaries, with the vapor sources at the southern boundaries originating from the Arabian Sea and Bay of Bengal and the vapor sources at the western boundary being transported by mid-latitude westerlies. The TP is a moisture sink at a climatological mean, with an annual average net water vapor flux of 11.86 × 10 6 kg • s −1 . Water vapor transport is much stronger in JJA than in other times of the year, and the net water vapor flux is 29.60 × 10 6 kg • s −1 . The net water vapor flux in the TP increased with a linear trend of 0.12×10 6 kg • s −1 • year −1 (α = 0.01), while the increase in the flux was more significant in JJA than in other times of the year with a linear trend of 0.30 ×10 6 kg • s −1 • year −1 (α = 0.01). Detailed features in the water vapor flux and transport changes across the TP's four boundaries were explored by simulating backward trajectories with a Lagrangian trajectory model (hybrid singleparticle Lagrangian integrated trajectory model, HYSPLIT). In the study period, the water vapor contribution rate of western channel is increased. However, the Southern channel's water vapor contribution decreased.

No abstract

Although bone cancer pain is still not fully understood by scientists and clinicians alike, studies suggest that toll like receptor 4 (TLR4) plays an important role in the initiation and/or maintenance of pathological pain state in bone cancer pain. A promising treatment for bone cancer pain is the downregulation of TLR4 by RNA interference; however, naked siRNA (small interference RNA) is not effective in long-term treatments. In order to concoct a viable prolonged treatment for bone cancer pain, an inducible lentivirus LvOn-siTLR4 (tetracycline inducible lentivirus carrying siRNA targeting TLR4) was prepared and the antinociception effects were observed in bone cancer pain rats induced by Walker 256 cells injection in left leg. Results showed that LvOn-siTLR4 intrathecal injection with doxycycline (Dox) oral administration effectively reduced the nociception induced by Walker 256 cells while inhibiting the mRNA and protein expression of TLR4. Proinflammatory cytokines as TNF-α and IL-1β in spinal cord were also decreased. These findings suggest that TLR4 could be a target for bone cancer pain treatment and tetracycline inducible lentivirus LvOn-siTLR4 represents a new potential option for long-term treatment of bone cancer pain.