Strategies to Reduce Morphine Tolerance in Cancer: Evaluation of the Bifunctional Opioid UFP-505

Morphine is a gold-standard analgesic acting at MOP (μ) opioid receptors, producing analgesia and tolerance when administered chronically to patients (e.g.,cancer patients). If DOP (δ) opioid receptors are blocked at the same time that MOP is activated then analgesia with reduced tolerance results. UFP-505 (H-Dmt-Tic-Gly-NH-Bzl) is a synthetic pseudopeptide that interacts with MOP and DOP receptors (bifunctional). In a series of different models, we have characterized the pharmacological profile of UFP- 505 and we evaluated its antinociceptive properties in vivo. In Chinese Hamster Ovary (CHO) cells stably expressing human MOP or DOP receptors, UFP-505 presented a full agonism and ultra-low partial agonism respectively. UFP-505 caused a concentration-dependent internalization of MOP receptors, in contrast to morphine. Additionally, UFP-505 caused DOP receptor internalization similar to the full DOP agonist DPDPE. In a series of tail-flick assays using Wistar rats, acute intrathecal (i.t.) 10nmol UFP-505 produced strong antinociception, similar to 10nmol i.t. morphine. After 3 days of repeated administration, UFP-505 did not produce antinociceptive tolerance, in contrast to morphine. In neuronal tissue of treated animals, UFP-505 caused varying changes to opioid receptor mRNA levels, similar to morphine. In the same model, UFP-505 induced MOP and DOP receptor internalization, whereas morphine failed to internalize the MOP receptors. UFP-505 also induced the internalization of MOP and DOP receptors in a novel CHO cell line stably expressing both receptors (produced as part of this project), in contrast to morphine. Collectively this thesis has made a significant contribution to the field in that: 1) an extensive pharmacological in vitro and in vivo characterization is made; 2) a MOPagonist/DOP-partial agonist is shown to produce strong antinociception with no tolerance. Further work on bifunctional opioids may lead to a better understanding of the mechanisms of analgesic tolerance and ligands like UFP-505 are good examples of prototypes for further development.