am-630 and Cancer-Pain

As inflammatory and immune responses are involved in pathophysiology of debilitating neuropathic pain, reagents that can modulate these two responses may have therapeutic potential. Morin, derived from the moraceae family of plants, benefits inflammation-related diseases, but its antinociceptive effects on cancer pain remain elusive. In the present study, we investigated antinociceptive effects of morin on bone cancer pain using a rat model, where rats were subject to implantation of Walker 256 mammary gland carcinoma cells into the tibia. Morin (5-20 mg/kg) dose-dependently attenuated behavioral hypersensitivities, including mechanical allodynia and free movement pain, which was accompanied by downregulation of astrocyte marker glial fibrillary acidic protein in the spinal cord in cancer-bearing rats. Treatment with morin also induced reduction of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and upregulation of an antiinflammatory cytokine IL-10. Furthermore, intrathecal injection of AM630 (an antagonist of cannabinoid receptor 2, CB

Topics: Animals; Astrocytes; Bone Neoplasms; Cancer Pain; Cytokines; Female; Flavonoids; Glial Fibrillary Acidic Protein; Hyperalgesia; Indoles; Inflammation; Injections, Spinal; Interleukin-10; Interleukin-1beta; Interleukin-6; Neoplasm Transplantation; Neuralgia; Pain Measurement; Rats; Rats, Sprague-Dawley; Spinal Cord; Tumor Necrosis Factor-alpha

Bufalin is a natural anti-inflammatory small molecule. Given the close relationship between inflammation and cancer, many scholars have studied the effect of bufalin on cancer in vitro, but in vivo research is still lacking. A murine bone cancer model was used in this study. We conducted pain sensitive test on mice with bone cancer, by nocifensive behavior, mechanical allodynia, and thermal hyperalgesia. Serum levels of bone loss markers with bufalin treatment were measured by ELISA. Expressions of osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL) were analyzed in bufalin-treated mice by real-time PCR and Western blot. Cannabinoid 2 receptor (CB2) inverse agonist AM630 was administrated to mice with bone cancer together with bufalin. Bufalin relieved cancer-induced pain and bone destruction in the murine bone cancer model. Serum levels of bone loss markers after bufalin treatment were reduced. Bufalin upregulated OPG and downregulated RANKL. The CB2 receptor inverse agonist, AM630, reduced the pain relief of bufalin treatment in the mouse bone cancer model. This study demonstrates that bufalin relieves cancer-induced pain and bone destruction, which is mediated through the CB2 receptor.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Bone and Bones; Bone Neoplasms; Bufanolides; Cancer Pain; Hyperalgesia; Indoles; Male; Mice; Osteoprotegerin; Pain Measurement; RANK Ligand; Receptor, Cannabinoid, CB2

Morphine is widely used as an analgesic to treat moderate to severe pain, but chronic morphine use is associated with development of tolerance and dependence, which limits its analgesic efficacy. Our previous research has showed that nonanalgetic dose of a cannabinoid type 2 (CB2) receptor agonist reduced morphine tolerance in cancer pain. A previous study showed the colocalization of CB2 and transient receptor potential vanilloid 1 (TRPV1) in human and rat dorsal root ganglia (DRG) sensory neurons. Whether coadministration of a CB2 receptor agonist and morphine could reduce TRPV1 expression in morphine‑induced antinociception and tolerance in cancer pain is unclear. Therefore, we investigated the effects of coadministration of a CB2 receptor agonist AM1241 and morphine on TRPV1 expression and tolerance in cancer pain. Coadministration of AM1241 and morphine for 8 days significantly reduced morphine tolerance, as assessed by measuring paw withdrawal latency to a radiant heat stimulation, in Walker 256 tumor‑bearing rats. Repeated morphine treatment for a period of 8 days induced upregulation of the TRPV1 protein expression levels in the DRG in the tumor‑bearing rats, although no change in mRNA expression. Pretreatment with AM1241 reduced this morphine‑induced upregulation of TRPV1 and the effect was reversed by the CB2 receptor antagonist AM630. Our findings suggest that coadministration of a CB2 receptor agonist AM1241 and morphine reduced morphine tolerance possibly through regulation of TRPV1 protein expression in the DRG in cancer pain.

Topics: Analgesics, Opioid; Animals; Cancer Pain; Cannabinoid Receptor Agonists; Cannabinoids; Disease Models, Animal; Down-Regulation; Drug Tolerance; Ganglia, Spinal; Indoles; Male; Morphine; Rats; Rats, Wistar; TRPV Cation Channels