Abstract
BACKGROUND: A major advancement in the field of analgesic pharmacology has been the development of G-protein-biased opioid agonists that display less respiratory depression than conventional drugs. It is uncertain, however, whether these new drugs cause less tolerance, hyperalgesia, and other maladaptations when administered repeatedly. METHODS: The archetypical µ-opioid receptor agonist morphine and, separately, the G-protein-biased µ-opioid receptor agonist oliceridine were administered to mice. These drugs were used in models of acute analgesia, analgesic tolerance, opioid-induced hyperalgesia, reward, and physical dependence. In addition, morphine and oliceridine were administered for 7 days after tibia fracture and pinning; mechanical allodynia and gait were followed for 3 weeks. Finally, the expression of toll-like receptor-4 and nacht domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NALP3) and interleukin-1β mRNA were quantified in spinal tissue to measure surgical and drug effects on glia-related gene expression. RESULTS: We observed using the tail flick assay that oliceridine was a 4-fold more potent analgesic than morphine, but that oliceridine treatment caused less tolerance and opioid-induced hyperalgesia than morphine after 4 days of ascending-dose administration. Using similar analgesic doses, morphine caused reward behavior in the conditioned place preference assay while oliceridine did not. Physical dependence was, however, similar for the 2 drugs. Likewise, morphine appeared to more significantly impair the recovery of nociceptive sensitization and gait after tibial fracture and pinning than oliceridine. Furthermore, spinal cord toll-like receptor-4 levels 3 weeks after fracture were higher in fracture mice given morphine than those given oliceridine. CONCLUSIONS: Aside from reduced respiratory depression, G-protein-biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery.