am-1241 and Bone-Neoplasms

We evaluated the pharmacology of spinal selective cannabinoid (CB) receptor agonists and a cyclooxygenase-2 (COX-2) inhibitor on bone tumor pain. MRMT-1 tumor cells were injected into the tibia of female Sprague-Dawley rats. MRMT-1 tumor cells produced a bone tumor confirmed by radiologic and histological findings. Intrathecal CB1 (ACEA) and CB2 receptor (AM 1241) agonists and a COX-2 inhibitor (DuP 697) dose-dependently increased the withdrawal threshold. The calculated ED50 (nmol/l) values for ACEA, AM 1241 and DuP 697 were 0.007, 2.3 and 76.1, respectively. Reverse transcriptase polymerase chain reaction and Western blot showed that COX-2 mRNA and protein, but not CB1 or CB2 receptor, were increased in the spinal cords of rats with bone tumors. Spinal CB1 receptor and CB2 receptor agonists and COX-2 inhibitor may be useful in the management of bone tumor pain. Furthermore, CB2 receptor agonist may be more potent than CB1 receptor agonist and COX-2 inhibitor.

Topics: Animals; Arachidonic Acids; Bone Neoplasms; Cannabinoid Receptor Agonists; Cannabinoids; Cell Line, Tumor; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Female; Hyperalgesia; Pain; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; RNA, Messenger; Spinal Cord; Thiophenes; Tibia

Cannabinoid CB(2) agonists have been shown to alleviate behavioral signs of inflammatory and neuropathic pain in animal models. AM1241, a CB(2) agonist, does not demonstrate central nervous system side effects seen with CB(1) agonists such as hypothermia and catalepsy. Metastatic bone cancer causes severe pain in patients and is treated with analgesics such as opiates. Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance bone destruction in a murine model of bone cancer. In contrast, CB(2) selective agonists have been shown to reduce bone loss associated with a model of osteoporosis. Here we tested whether a CB(2) agonist administered over a 7day period inhibits bone cancer-induced pain as well as attenuates cancer-induced bone degradation.. A murine bone cancer model was used in which osteolytic sarcoma cells were injected into the intramedullary space of the distal end of the femur. Behavioral and radiographic image analysis was performed at days 7, 10 and 14 after injection of tumor cells into the femur.. Osteolytic sarcoma within the femur produced spontaneous and touch evoked behavioral signs of pain within the tumor-bearing limb. The systemic administration of AM1241 acutely or for 7days significantly attenuated spontaneous and evoked pain in the inoculated limb. Sustained AM1241 significantly reduced bone loss and decreased the incidence of cancer-induced bone fractures.. These findings suggest a novel therapy for cancer-induced bone pain, bone loss and bone fracture while lacking many unwanted side effects seen with current treatments for bone cancer pain.

Topics: Analgesics; Animals; Bone Neoplasms; Bone Resorption; Cannabinoids; Disease Models, Animal; Femoral Neoplasms; Femur; Fractures, Bone; Male; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Pain; Radiography; Receptor, Cannabinoid, CB2; Sarcoma

The activation of CB(2) receptors induces analgesia in experimental models of chronic pain. The present experiments were designed to study whether the activation of peripheral or spinal CB(2) receptors relieves thermal hyperalgesia and mechanical allodynia in two models of bone cancer pain.. NCTC 2472 osteosarcoma or B16-F10 melanoma cells were intratibially inoculated to C3H/He and C57BL/6 mice. Thermal hyperalgesia was assessed by the unilateral hot plate test and mechanical allodynia by the von Frey test. AM1241 (CB(2) receptor agonist), AM251 (CB(1) receptor antagonist), SR144528 (CB(2) receptor antagonist) and naloxone were used. CB(2) receptor expression was measured by Western blot.. AM1241 (0.3-10 mg.kg(-1)) abolished thermal hyperalgesia and mechanical allodynia in both tumour models. The antihyperalgesic effect was antagonized by subcutaneous, intrathecal or peri-tumour administration of SR144528. In contrast, the antiallodynic effect was inhibited by systemic or intrathecal, but not peri-tumour, injection of SR144528. The effects of AM1241 were unchanged by AM251 but were prevented by naloxone. No change in CB(2) receptor expression was found in spinal cord or dorsal root ganglia.. Spinal CB(2) receptors are involved in the antiallodynic effect induced by AM1241 in two neoplastic models while peripheral and spinal receptors participate in the antihyperalgesic effects. Both effects were mediated by endogenous opiates. The use of drugs that activate CB(2) receptors could be a useful strategy to counteract bone cancer-induced pain symptoms.

Topics: Analgesics; Animals; Bone Neoplasms; Camphanes; Cannabinoids; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Ganglia, Spinal; Humans; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Naloxone; Osteosarcoma; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB2; Spinal Cord