Metastatic breast cancer spreads principally to long bones like femur. The presence of breast cancer metastasis in bone microenvironment results in severe pain increasing with disease progression. Opioids, including morphine, are a standard for bone cancer pain management despite their adverse effects at high doses. Our aim here was to examine the effects of opioidergic-independent neurotensin (NT) receptor (NTS1, NTS2) activation in alleviating bone cancer pain in a new clinically relevant mouse model. To this end, neurotensinergic agonists (PD149163, JMV-2012 or JMV-431) were intrathecally administrated to C57BL/6 mice implanted with syngenic E0771 metastatic breast cancer cells in the femoral intramedullary canal. Compounds were analysed for touch-evoked (von Frey), forced movement-evoked (Rotarod) and ambulatory (dynamic weight bearing) pain 18 days following E0771 implantation. The intrathecal injection of PD149163, a NTS1-selective agonist, induced a marked decrease of touch-evoked pain reaching 64 ± 9%. On the Rotarod, PD149163 treatment failed to improve either time spent on the rotating cylinder or the visual pain score. The injection of a non-selective agonist, JMV-2012, reduced touch-evoked pain of 16 ± 5%, but was not efficient in reversing pain under a physical effort on the Rotarod. JMV-431, a NTS2-selective agonist, produced a significant reduction of touch-evoked pain of 70 ± 9% in cancer mice, which also spent more time (10 ± 13%) on the Rotarod and expressed less movement-evoked pain (97 ± 20%) than saline-treated cancer mice. However, acute spinal JMV-431 failed to restore ipsilateral weight bearing toward basal values. The analysis of spinal neuronal activity of mice injected with JMV-431 showed a significant reduction of 55 ± 6% of c-Fos expression in laminae V-VII of the ipsilateral horn 18 days post implantation. In conclusion, these results indicate that the NTS2 receptor represents a promising target for treating bone cancer pain. Further investigations of continuous delivery of NTS2-selective agonists at the central and peripheral levels are under way to evaluate the real potential of these compounds for prophylactic and curative treatments against cancer pain.

Supported by CIHR/Canadian Pain Society/AstraZeneca and Cancer Research Society grants.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-03-08.

2010