Pharmacological Characters of Oliceridine, a μ-Opioid Receptor G-Protein[FIGURE DASH]Biased Ligand in Mice

BACKGROUND: A major advancement in the field of analgesic pharmacology has been the development of G-protein[FIGURE DASH]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[FIGURE DASH]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[FIGURE DASH]biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery. Accepted for publication June 12, 2018. Funding: This study was supported by VA Merit Review Grant I01BX000881 to J.D.C. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to De-Yong Liang, PhD, and J. David Clark, MD, PhD, Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, CA. Address e-mail to dyliang@stanford.edu and djclark@stanford.edu. © 2018 International Anesthesia Research Society

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