Cancer-related bone pain is attenuated by a systemically available δ-opioid receptor agonist

Patients with bone cancer report severe pain and receive mu-opioids. We developed a family of peptidomimetic delta-agonists, one of which H,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 (I 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 8 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 8 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. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.