RT Journal Article SR Electronic T1 TRV0109101, a G Protein-Biased Agonist of the µ-Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 254 OP 262 DO 10.1124/jpet.117.241117 VO 362 IS 2 A1 Michael Koblish A1 Richard Carr III A1 Edward R. Siuda A1 David H. Rominger A1 William Gowen-MacDonald A1 Conrad L. Cowan A1 Aimee L. Crombie A1 Jonathan D. Violin A1 Michael W. Lark YR 2017 UL http://jpet.aspetjournals.org/content/362/2/254.abstract AB Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients with OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage. The development of OIH and tolerance tend to occur simultaneously and, thus, present a challenge when studying the molecular mechanisms driving each phenomenon. We tested the hypothesis that a G protein-biased µ-opioid peptide receptor (MOPR) agonist would not induce symptoms of OIH, such as mechanical allodynia, following chronic administration. We observed that the development of opioid-induced mechanical allodynia (OIMA), a model of OIH, was absent in β-arrestin1−/− and β-arrestin2−/− mice in response to chronic administration of conventional opioids such as morphine, oxycodone and fentanyl, whereas tolerance developed independent of OIMA. In agreement with the β-arrestin knockout mouse studies, chronic administration of TRV0109101, a G protein-biased MOPR ligand and structural analog of oliceridine, did not promote the development of OIMA but did result in drug tolerance. Interestingly, following induction of OIMA by morphine or fentanyl, TRV0109101 was able to rapidly reverse allodynia. These observations establish a role for β-arrestins in the development of OIH, independent of tolerance, and suggest that the use of G protein-biased MOPR ligands, such as oliceridine and TRV0109101, may be an effective therapeutic avenue for managing chronic pain with reduced propensity for opioid-induced hyperalgesia.