Abstract
It has previously been suggested that the upregulation of GluN2B-containing N-methyl D-aspartate receptors (GluN2B) within the rostral anterior cingulate cortex (rACC) may contribute to the development of chronic pain. The present study used a rat model of bone cancer pain in order to investigate whether lentiviral-mediated delivery of small interfering RNAs targeting GluN2B (LV-GluN2B) could attenuate pain associated with bone cancer, by selectively decreasing GluN2B expression within the rACC. Sprague Dawley rats were inoculated with osteosarcoma cells into the intramedullary space of the right tibia in order to induce persistent bone cancer-associated pain. Intra-rACC administration of the lentiviral siRNA was performed in the tumor bearing rats; and reverse transcription-quantitative polymerase chain reaction and western blotting were performed in order to detect the expression levels of GluN2B. Pain behavior changes were evaluated via paw withdrawal threshold and latency determinations. Marked and region-selective decreases in the mRNA and protein expression levels of GluN2B were detected in the rACC following the intra-rACC administration of LV-GluN2B. Furthermore, the rats also exhibited pain behavior changes corresponding to the decreased levels of GluN2B. By post-operative day 14, inoculation of osteosarcoma cells had significantly enhanced mechanical allodynia and thermal hyperalgesia in the rats, which were subsequently attenuated by the intra-rACC administration of LV-GluN2B. Notably, the paw withdrawal threshold and latency of the tumor-bearing rats had recovered to normal levels, by day 14 post-administration. The results of the present study suggest that GluN2B within the rACC may be a potential target for RNA interference therapy for the treatment of pain associated with bone cancer. Furthermore, the lentiviral vector delivery strategy may be a promising novel approach for the treatment of bone cancer pain.
Highlights
Occurring in ~90% of patients during their illness [1], pain is one of the most common symptoms associated with cancer
The results of the present study suggest that GluN2B-containing N-methyl D-aspartate receptors (GluN2B) within the rostral anterior cingulate cortex (rACC) may be a potential target for RNA interference therapy for the treatment of pain associated with bone cancer
Long‐term increases in the synaptic insertion of glutamate receptor (GluR)1 subunits in rACC neurons may be induced by peripheral inflammation, which subsequently increases synaptic transmission during chronic pain [8]
Summary
Occurring in ~90% of patients during their illness [1], pain is one of the most common symptoms associated with cancer. In a mouse model of neuropathic pain, a previous study demonstrated that peripheral nerve injury may trigger both long‐term presynaptic and postsynaptic enhancement of excitatory synaptic transmission in layer II/III neurons within the rACC [7]. Long‐term increases in the synaptic insertion of glutamate receptor (GluR) subunits in rACC neurons may be induced by peripheral inflammation, which subsequently increases synaptic transmission during chronic pain [8]. These results suggest that long‐term changes in the plasticity of rACC neurons may have important roles in the development and maintenance of bone cancer‐associated pain
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