The objective of this study was to explore the potential role of G-protein-coupled receptor kinase 2 (GRK2) in the progression of cannabinoid 2 receptor (CB2) agonist-induced analgesic effects of bone cancer pain. Female Sprague–Dawley rats, weighing 160–180 g, were utilized to establish a model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. JWH-015, a selective CB2 agonist, was injected intrathecally or intraperitoneally on postoperative day 10. Bone cancer-induced pain behaviors—mechanical allodynia and ambulatory pain—were assessed on postoperative days −1 (baseline), 4, 7, and 10 and at post-treatment hours 2, 6, 24, 48, and 72. The expressions of spinal CB2 and GRK2 protein were detected by Western Blotting on postoperative days −1 (baseline), 4, 7, and 10 and at post-treatment hours 6, 24, and 72. The procedure produced prolonged mechanical allodynia, ambulatory pain, and different changes in spinal CB2 and GRK2 expression levels. Intrathecal or intraperitoneal administration of JWH-015 alleviated the induced mechanical allodynia and ambulatory pain, and inhibited the downregulation of spinal GRK2 expression. These effects were in a time-dependent manner and reversed by pretreatment of CB2 selective antagonist AM630. The results affirmed CB2 receptor agonists might serve as new treatment targets for bone cancer pain. Moreover, spinal GRK2 was an important regulator of CB2 receptor agonist-analgesia pathway.
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This research was supported by the National Natural Science Foundation of China (81371207, 81070892, 81171048 and 81171047) and a grant from the Department of Health of Jiangsu Province of China (XK201140, RC2011006).
All of the authors read and approved the final manuscript. CEL made substantial contributions to the experiments. BLH and LYS were mainly involved in the pain behavioral tests. BS and YZ performed the surgical procedure, administration of drugs, and Western blots studies; YES, CEL, and BLH were responsible for statistical analyses. All of these individuals participated in drafting the manuscript. XPG and ZLM conceived the idea, designed the study, and helped revise the manuscript.
Conflicts of Interest Statement
All of the authors declare no conflicts of interest.
Cui’e Lu, Linyu Shi, and Bei Sun have been contributed equally to this work.
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Lu, C., Shi, L., Sun, B. et al. A Single Intrathecal or Intraperitoneal Injection of CB2 Receptor Agonist Attenuates Bone Cancer Pain and Induces a Time-Dependent Modification of GRK2. Cell Mol Neurobiol 37, 101–109 (2017). https://doi.org/10.1007/s10571-016-0349-0
- Spinal cord
- Bone cancer pain