Pharmacological Characterization of Levorphanol, a G-Protein Biased Opioid Analgesic

BACKGROUND: Levorphanol is a potent analgesic that has been used for decades. Most commonly used for acute and cancer pain, it also is effective against neuropathic pain. The recent appreciation of the importance of functional bias and the uncovering of multiple µ opioid receptor splice variants may help explain the variability of patient responses to different opioid drugs. METHODS: Here, we evaluate levorphanol in a variety of traditional in vitro receptor binding and functional assays. In vivo analgesia studies using the radiant heat tail flick assay explored the receptor selectivity of the responses through the use of knockout (KO) mice, selective antagonists, and viral rescue approaches. RESULTS: Receptor binding studies revealed high levorphanol affinity for all the μ, δ, and κ opioid receptors. In 35S-GTPγS binding assays, it was a full agonist at most µ receptor subtypes, with the exception of MOR-1O, but displayed little activity in β-arrestin2 recruitment assays, indicating a preference for G-protein transduction mechanisms. A KO mouse and selective antagonists confirmed that levorphanol analgesia was mediated through classical µ receptors, but there was a contribution from 6 transmembrane targets, as illustrated by a lower response in an exon 11 KO mouse and its rescue with a virally transfected 6 transmembrane receptor splice variant. Compared to morphine, levorphanol had less respiratory depression at equianalgesic doses. CONCLUSIONS: While levorphanol shares many of the same properties as the classic opioid morphine, it displays subtle differences that may prove helpful in its clinical use. Its G-protein signaling bias is consistent with its diminished respiratory depression, while its incomplete cross tolerance with morphine suggests it may prove valuable clinically with opioid rotation. Accepted for publication February 9, 2018. Funding: This study was supported by grants from the National Institute on Drug Abuse (DA006241, DA007242), the Peter McManus Charitable Trust, Mayday Fund and Relmada Therapeutics, Inc (to G.W.P.), a core grant from the National Cancer Institute to MSKCC (CA008748), and the National Natural Science Foundation of China (81673412 to Z.L). The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Gavril W. Pasternak, MD, PhD, Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065. Address e-mail to pasterng@mskcc.org. © 2018 International Anesthesia Research Society

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