Chronic high dose P2X7 receptor inhibition exacerbates cancer-induced bone pain.

The functional role of P2X7 receptor (P2X7R) inhibition in cancer-induced bone pain has been highly contradictory. Whereas knockout studies have suggested pro-nociceptive effects, pharmacological studies suggest anti-nociceptive or no effect. The discrepancy is likely linked to the highly polymorphic nature of the P2X7R and the related functional differences in different tissue and conditions. In this study we tested the analgesic potential of AFC5261, a selective P2X7R antagonist, in a rat model of cancer-induced bone pain to evaluate if the opposing pro- and anti-nociceptive effects could be a consequence of long vs. short term inhibition of the P2X7R. Following intratibial inoculation of MRMT-1 carcinoma cells, movement-evoked and background pain was assessed with the limb use and weight-bearing test, and the effect of acute and chronic AFC5261-treatement evaluated. Bone degradation and tumor progression was in addition evaluated with x-ray densitometry and bioluminescence, respectively. In an acute treatment regime, a single administration of 300 mg/kg AFC5261 had no effect on either weight-bearing or limb use deficits. In contrast, morphine significantly increased both the limb use and weight-bearing ratio. In a chronic treatment study, BID administration of 300 mg/kg AFC5261 exacerbated the pain-related behavior, demonstrated by an earlier onset of both limb use and weight-bearing deficits without affecting the overall bone degradation or tumor progression. In contrast, 50 mg/kg and 100 mg/kg AFC5261 had no effect on the pain-related behavior. Overall, the data suggest that whereas acute P2X7R inhibition has no effect on the pain-related behavior, chronic inhibition exacerbate the cancer-induced bone pain.

Effect of sex in the MRMT-1 model of cancer-induced bone pain.

An overwhelming amount of evidence demonstrates sex-induced variation in pain processing, and has thus increased the focus on sex as an essential parameter for optimization of in vivo models in pain research. Mammary cancer cells are often used to model metastatic bone pain in vivo, and are commonly used in both males and females. Here we demonstrate that compared to male rats, female rats have an increased capacity for recovery following inoculation of MRMT-1 mammary cells, thus potentially causing a sex-dependent bias in interpretation of the data.