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.