title: Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain.
abstract: Opioid drugs like morphine and fentanyl are the gold standard for treating moderate to severe acute and chronic pain. However, opioid drug use can be limited by serious side effects, including constipation, tolerance, respiratory suppression, and addiction. For more than 100 years, we have tried to develop opioids that decrease or eliminate these liabilities, with little success. Recent advances in understanding opioid receptor signal transduction have suggested new possibilities to activate the opioid receptors to cause analgesia, while reducing or eliminating unwanted side effects. These new approaches include designing functionally selective ligands, which activate desired signaling cascades while avoiding signaling cascades that are thought to provoke side effects. It may also be possible to directly modulate downstream signaling through the use of selective activators and inhibitors. Separate from downstream signal transduction, it has also been found that when the opioid system is stimulated, various negative feedback systems are upregulated to compensate, which can drive side effects. This has led to the development of multi-functional molecules that simultaneously activate the opioid receptor while blocking various negative feedback receptor systems including cholecystokinin and neurokinin-1. Other novel approaches include targeting heterodimers of the opioid and other receptor systems which may drive side effects, and making endogenous opioid peptides druggable, which may also reduce opioid mediated side effects. Taken together, these advances in our molecular understanding provide a path forward to break the barrier in producing an opioid with reduced or eliminated side effects, especially addiction, which may provide relief for millions of patients.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ; Department of Chemistry and Biochemistry, College of Science, University of Arizona, Tucson, AZ.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Olson
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ.
authors.forename: Wei
authors.initials: W
authors.lastname: Lei
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ.
authors.forename: Attila
authors.initials: A
authors.lastname: Keresztes
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ.
authors.forename: Justin
authors.initials: J
authors.lastname: LaVigne
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ.
authors.forename: John M
authors.initials: JM
authors.lastname: Streicher
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy*; D055808:Drug Discovery; D006801:Humans
chemical_list: D000701:Analgesics, Opioid
keywords: Chronic Pain; Drug Discovery; Functional Selectivity; Novel Strategies; Novel Targets; Opioid