ABSTRACT
The focus of this work was to examine the potential role of p38 mitogen activated protein kinase (p38) in a mouse model of bone cancer (osteosarcoma) pain. To generate osteosarcoma and sham animals, osteosarcoma cells or medium were injected into the medullary canal of the femur. Initially, ipsilateral tactile allodynia was observed in both groups, but by 12 days post-surgery, thresholds in the sham group returned towards baseline while hypersensitivity in the osteosarcoma group lasted throughout the study. An increase in phosphorylated p38 was detected by western blotting in dorsal root ganglia (DRG) and spinal cord day 14 after surgery. Immunohistochemistry showed that p38 was phosphorylated in DRG and spinal dorsal horn neurons at this time point. Two doses of a selective p38 inhibitor, SCIO-469, were administered in the chow starting 5 days post-surgery and continued throughout the study. Treatment with SCIO-469 led to a decrease in osteosarcoma-induced clinical score but had no effect on the allodynia. Bone erosion and tumor growth were also examined but no significant reduction of bone erosion or tumor growth was observed in the SCIO-469 treated mice. These data suggest that the p38 signaling pathway does not play a major role in bone cancer-mediated pain.
Subject(s)
Bone Neoplasms/complications , Bone Neoplasms/enzymology , Enzyme Inhibitors/therapeutic use , Indoles/therapeutic use , Osteosarcoma/complications , Osteosarcoma/enzymology , Pain/enzymology , Pain/etiology , p38 Mitogen-Activated Protein Kinases/physiology , Animals , Behavior, Animal/drug effects , Body Weight/physiology , Cell Line, Tumor , Eating/drug effects , Eating/physiology , Enzyme Activation/physiology , Ganglia, Spinal/enzymology , Immunohistochemistry , Male , Mice , Mice, Inbred C3H , Neoplasm Transplantation , Pain/drug therapy , Pain Measurement/drug effects , Sensory Thresholds/drug effects , Tomography, X-Ray Computed , Vocalization, Animal/drug effects , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
Patients with bone cancer report severe pain and receive mu-opioids. We developed a family of peptidomimetic delta-agonists, one of which H2N-Tyr-dVal-Gly-Phe-Ala-OH ([dVal(L)2,Ala(L)5]E) binds with a 1700x affinity at the delta versus mu receptor. To examine the systemic analgesic efficacy of this delta-agonist versus morphine in osteosarcoma pain, osteosarcoma cells are injected into one femur of the anesthetized mouse. After 10-18 days, a decalcification of the injected femur occurs along with a pronounced tactile allodynia. IP morphine and [dVal(L)2,Ala(L)5]E produced a dose-dependent reversal of allodynia with the respective ED50 values being 5.3+/-1.9 mg/kg for morphine and 1.3+/-0.3 mg/kg for [dVal(L)2,Ala(L)5]E. Plotting peak effect versus area under the analgesic curve for doses of morphine and [dVal(L)2,Ala(L)5]E revealed overlapping curves suggesting that for a given effect, [dVal(L)2,Ala(L)5]E produced a similar duration of action as morphine. These effects were reversed by IP naloxone (3 mg/kg). IP naltrindole (1 mg/kg) preferentially reversed [dVal(L)2,Ala(L)5]E. The upper dose effects of morphine but not [dVal(L)2,Ala(L)5]E were limited by pronounced hyperactivity. No other effects were noted. These results show that IP [dVal(L)2,Ala(L)5]E through a delta receptor produces analgesia equal in efficacy to that of morphine but with a 4.5-fold greater potency. Over the doses examined, morphine actions were side effect limited. The delta side effects were not so limited, suggesting a favorable therapeutic ratio for delta-agonists in this pain model. These studies suggest that a systemically delivered delta-opioid agonist has pronounced analgesic properties on a preclinical cancer pain model.
