Abstract ID: A27
Abstract Title: Systemic Delta-Opioid Receptor Agonist Attenuates Hyperalgesia in a Murine Osteosarcoma Pain Model
Poster Type: Poster
ABSTRACT BODY
Severe pain is present in a major proportion of patients suffering from primary or metastatic bone cancer. Opiates are a valued part of the therapeutic regime for such patients with moderate to severe pain. Although systemic µ opioids such as morphine are widely used, the use of these agents is limited by unwanted side-effects including sedation, hallucinations, respiratory depression, and severe constipation. Agents that are active at the ∂ opioid receptor have been shown to be effective against inflammatory and neuropathic pain in animal models when delivered intrathecally. The peptidic structure of most ∂-agonists however typically limits their central bioavailability after systemic delivery. Recently, we have developed peptidomimetic δ-agonists that cross the blood-brain barrier. Preliminary studies have shown that one such compound, designated as GO3130 (Tyr-c[D-ValL-Gly-D-Phe-AlaL]-OH) , has high selectivity for the δ opioid receptor with a binding affinity of approximately 1700-fold greater for the δ than the μ opioid receptor. We sought to determine the analgesic efficacy of such agents as compared to morphine in a well defined preclinical model of cancer pain. In this model, 20μl of cultured syngeneic ostesarcoma cells are injected through a burr hole in the right femur of the anesthetized male mouse of approximately 25 grams. The burr hole is sealed with dental amalgam. Over the ensuing 10-18 days, this leads to a progressive decalcification of the injected femur as defined by x-ray and a corresponding appearance of a pronounced tactile allodynia in the injected leg. We have tested the systemic efficacy of the µ agonists morphine and the ∂ agonist GO3130 on the induced tactile allodynia in the osteosarcoma mouse. In these studies, intraperitoneal delivery of morphine and GO3130 resulted in a dose dependent reversal of the allodynia with the respective ED 50 values being 8.26±0.002 mg/kg for morphine and 1.34±0.31 mg/kg for GO3130. Plotting the Peak Effect vs Area Under the Analgesic Curve for different doses of morphine and GO3130 revealed overlapping curves suggesting that for a given effect GO3130 produced a similar duration of effect as that produced by morphine, indicating peptidomimetic kinetics similar to those associated with the alkaloid. The upper dose effects of morphine were limited by the appearance of pronounced hyperactivity. The hyperactivity observed after equianalgesic doses of GO3130 were substantially less. These studies suggest for the first time that that a systemically delivered ∂ selective opioid agonists has pronounced analgesic properties on a cancer animal model. (R01 DA05539.)
References:
Goodman M, Zapf C, and Rew Y (2001) New reagents, reactions and peptidomimetics for drug design. Biopolymers 60:229-245.
Svensson CI, Rew Y, Malkmus S, Sciller PW, Taulane JP, Goodman M, and Yaksh TL (2003) Systemic and spinal analgesic activity of a ?-opioid-selective lanthionine enkephalin analog. JPET 304:827-32.
Yaksh TL (1997) Pharmacology and mechanisms of opioid analgesic activity. Anesthesia: Biological Foundations. Lippincott-Raven:921-34.
ATTACHED FILES
Reg Anesth Pain Med 2004; 29(2):A27