Cancer-related bone pain is attenuated by a systemically available delta-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 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.
Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
Josue
J
Brainin-Mattos
Nicole D
ND
Smith
Shelle
S
Malkmus
Yosup
Y
Rew
Murray
M
Goodman
Joseph
J
Taulane
Tony L
TL
Yaksh
D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D018771:Arthralgia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D001859:Bone Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009020:Morphine / Q000008:administration & dosage; D012516:Osteosarcoma / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D014110:Touch; D016896:Treatment Outcome
D000700:Analgesics; D017465:Receptors, Opioid, delta; D009020:Morphine