P2X7 receptor-deficient mice are susceptible to bone cancer pain
Rikke Rie Hansen1, Christian K Nielsen, Arafat Nasser
1Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, Copenhagen University, Copenhagen, Denmark Center for Ageing and Osteoporosis, Research Centre Glostrup, Glostrup Hospital, Denmark Odense University Hospital, University of Southern Denmark, Odense, Denmark Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. Furthermore, acute treatment with the selective P2X7 receptor antagonist, A-438079, failed to alleviate pain-related behaviours in models of bone cancer pain with and without astrocyte activation (BALB/cJ or C3H mice inoculated with 4T1 mammary cancer cells or NCTC 2472 osteosarcoma cells, respectively), suggesting that astrocytic P2X7 receptors play a negligible role in bone cancer pain. The results support the hypothesis that bone cancer pain is a separate pain state compared with those of neuropathic and inflammatory pain. However, the recent discovery of a P2X7 receptor splice variant expressed in the knockout mice used for this study complicates the interpretation of the results. The P2X7 splice variant receptor was detected in the spinal cord but not in osteoclasts of the P2X7R KO mouse. Further experiments are needed to elucidate the exact role of the P2X7 receptors in bone cancer pain.
Insights
Bone cancer pain mechanisms differ from neuropathic and inflammatory pain. P2X7 receptor knockout mice showed increased susceptibility, and antagonists were ineffective, suggesting a complex role requiring further study.
Area of Science:
- Pain research
- Oncology
- Neuroscience
Background:
- The purinergic P2X7 receptor (P2X7R) is involved in neuropathic and inflammatory pain.
- Its role in bone cancer pain remains unclear.
- P2X7R is a potential therapeutic target for pain management.
Purpose of the Study:
- To investigate the role of P2X7R in bone cancer pain.
- To determine if P2X7R antagonism alleviates bone cancer pain.
- To assess the contribution of astrocytic P2X7R in bone cancer pain.
Main Methods:
- Utilized P2X7 receptor knockout (P2X7R KO) BALB/cJ mice.
- Administered the selective P2X7R antagonist A-438079.
- Employed mouse models of bone cancer pain using 4T1 mammary cancer and NCTC 2472 osteosarcoma cells.
Main Results:
- P2X7R KO mice exhibited increased susceptibility and earlier onset of bone cancer pain.
- A-438079 treatment did not alleviate pain-related behaviors.
- Astrocytic P2X7R appeared to play a negligible role in bone cancer pain.
Conclusions:
- Bone cancer pain may be a distinct pain state compared to neuropathic and inflammatory pain.
- The interpretation of P2X7R KO results is complicated by a detected splice variant.
- Further research is necessary to fully elucidate the function of P2X7 receptors in bone cancer pain.
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