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.
Bone cancer (osteosarcoma) often leads to chronic pain characterized by episodes of breakthrough pain as well as mechanical allodynia. Emerging data suggest that p38 mitogen-activated protein kinase (p38) regulates induction and maintenance of hypersensitivity in different painful pathological conditions. To study the potential role of p38 in bone cancer pain, we examined the expression and activation of p38 in dorsal root ganglia (DRG) and spinal cord in a mouse osteosarcoma model. To generate osteosarcoma and control (sham) animals, osteolytic sarcoma cells or medium was injected into the medullary canal of right femur. Initially, ipsilateral tactile allodynia was observed in both groups but 10 days after surgery thresholds in the sham group returned to baseline while hypersensitivity in the osteosarcoma group lasted throughout the study. Development of tactile allodynia in osteosarcoma mice correlated with increased osteolysis, assessed by x-ray. Western blot data indicated that there was an increase in phosphorylated p38 (P-p38) during the initial phase (day 2-7) in ipsilateral DRGs (L4-L6) and lumbar spinal cord in tumor-bearing mice as well as in sham mice. However, at later timepoints (day 14-17) increased P-p38 was observed only in osteosarcoma mice. Immunocytochemistry showed that phosphorylation of p38 occurred predominantly in small and medium sized neurons in DRGs and in lamina I and II neurons of the spinal dorsal horn, but to some extent also in microglia in the spinal cord parenchyma. No activation of p38 was observed in astrocytes. Single bolus intraperitoneal injection (100 mg/ kg) of p38 MAPK inhibitor SB202190 (active), but not SB202474 (inactive), at day 17 post-surgery resulted in significant reversal of tactile allodynia in osteosarcoma mice. These data suggest that the p38 MAPK signaling pathway may play an important role in bone cancer-mediated pain, and that inhibition of p38 MAPK activity may provide therapeutic benefits in cancer pain management.
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