Opioid Research
Sadee and coworkers have discovered that the m opioid receptor (MOR) can exist in a ligand-free spontaneous signaling and that prolonged exposure to opioids leads to enhanced and protracted basal signaling. We hypothesize that such elevated basal signaling drives opioid dependence and possibly other manifestations of opioid use disorder (OUD, leading to high sensitivity to inverse opioid antagonists (that block basal signaling, e.g., naltrexone, naloxone) in causing withdrawal. Recently, we have discovered that 6b-naltrexol (6BN, main metabolite of naltrexone) is a neutral MOR antagonist (binds but does not block basal MOR activity). In addition, we hypothesize that 6BN favors the non-signaling ground state of MOR, thereby, gradually reversing the elevated basal MOR activity to the opioid-naïve ground state – and also reversing dependence at doses that do not interfere with opioid pain therapy nor cause withdrawal in dependent persons. This hypothesis of a novel mechanism of MOR modulation could lead to the discovery of a novel class of OUD modulators, with clinical implication for OUD and pain therapies.
Select publications on opioids include:
W. Sadee, J.C. McKew. Ligand-Free Signaling of G-Protein-Coupled Receptors: Relevance to μ Opioid Receptors in Analgesia and Addiction. Molecules 2022,27,5826. https://doi.org/ 10.3390/molecules27185826
Sadee, J. Oberdick, Z. Wang. Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management. Preprints 2020, 2020080017 (doi: 10.20944/preprints202008.0017.v1). Molecules 25, 4163; doi:10.3390/molecules25184163 (2020).
Safa, A.R. Lau, S., Aten, K. Schilling, K.L. Bales, V. Miller, J. Fitzgerald, M. Chen, K. Hill, K. Dzwigalski, K. Obrietan, M.A. Phelps, W. Sadee, J. Oberdick. Pharmacological prevention of neonatal opioid withdrawal in a pregnant guinea pig model. bioRxiv, preprint mdpi doi: https://doi.org/10.1101/2020.07.25.221192. Front.Pharmacology, DOI: 10.3389/fphar.2020.613328 (2021).
Oberdick, Y. Ling, M.A. Phelps, M.S. Yudovich, K. Schilling, W. Sadee. Preferential delivery of an opioid antagonist to the fetal brain in pregnant mice. J.Pharmacol.Exp.Ther. 358: 22-30 (2016). PMID:27189967
Yancey-Wrona, T.J. Raymond, H.K. Mercer, W. Sadee, E.J. Bilsky 6β-Naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: An exploratory study. Pain Medicine 12: 1727-1737 (2011).
Yancey-Wrona, T.J. Raymond, H.K Mercer, W. Sadee, E.J. Bilsky. 6ß-Naltrexol preferentially antagonizes opioid effects on gastrointestinal transit compared to antinociception in mice. Life Sci., 413-420 (2009).
Wang, X. Sun, W. Sadee. Different effects of opioid antagonists on mu, delta, and kappa opioid receptors with and without agonist pretreatment. J.Pharmacol.Exp.Ther 321: 544-552 (2007).
Wang, X. Sun, L.M. Bohn, W. Sadée. Opioid receptor homo- and hetero-dimerization in living cells by quantitative bioluminescence resonance Energy Transfer. Molec.Pharmacol. 67: 2173-2184 (2005).
K.M. Raehal, J.J. Lowery, C.M. Bhamidipati, R.M. Paolino, D. Wang, W. Sadée, E.J. Bilsky. In vivo characterization of 6ß-naltrexol, an opioid ligand with less inverse agonist activity compared to naltrexone and naloxone in opioid dependent mice. J.Pharmacol.Exper.Ther. 313: 1150 1162 (2005).
Wang, K.M. Raehal, E.T. Lin, J.J. Lowery, B.L. Kieffer, E.J. Bilsky, W. Sadée. Basal Signaling Activity of m Opioid Receptor in Mouse Brain: Role in Narcotic Dependence. J.Pharmacol.Exp.Ther. 308: 1-9 (2004).
Wang, K.M. Raehal, E.J. Bilsky, W. Sadée. Inverse agonists and neutral antagonists at m opioid receptor (MOR): Possible role of basal receptor signaling in narcotic dependence. J.Neurochem., 77: 1590-1600 (2001).