title: Molecular Pharmacology of δ-Opioid Receptors.
abstract: Opioids are among the most effective analgesics available and are the first choice in the treatment of acute severe pain. However, partial efficacy, a tendency to produce tolerance, and a host of ill-tolerated side effects make clinically available opioids less effective in the management of chronic pain syndromes. Given that most therapeutic opioids produce their actions via µ-opioid receptors (MOPrs), other targets are constantly being explored, among which δ-opioid receptors (DOPrs) are being increasingly considered as promising alternatives. This review addresses DOPrs from the perspective of cellular and molecular determinants of their pharmacological diversity. Thus, DOPr ligands are examined in terms of structural and functional variety, DOPrs' capacity to engage a multiplicity of canonical and noncanonical G protein-dependent responses is surveyed, and evidence supporting ligand-specific signaling and regulation is analyzed. Pharmacological DOPr subtypes are examined in light of the ability of DOPr to organize into multimeric arrays and to adopt multiple active conformations as well as differences in ligand kinetics. Current knowledge on DOPr targeting to the membrane is examined as a means of understanding how these receptors are especially active in chronic pain management. Insight into cellular and molecular mechanisms of pharmacological diversity should guide the rational design of more effective, longer-lasting, and better-tolerated opioid analgesics for chronic pain management.
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Centre de Recherche du CHU de Sherbrooke, Centre d'excellence en neurosciences de l'Univeristé de Sherbrooke, and Institut de Pharmacologie de Sherbrooke, Sherbrooke, Quebec, Canada (L.G.); Québec Pain Research Network, Sherbrooke, Quebec, Canada (L.G.); Departments of Anesthesiology and Perioperative Care and Pharmacology, University of California, Irvine, California (C.M.C.); Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.M.C.); Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, California (M.v.Z.); Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montréal, Montreal, Quebec, Canada (P.W.S.); and Departments of Psychiatry, Pharmacology, and Neurosciences, Faculty of Medicine, University of Montréal and Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada (G.P.).
authors.forename: Louis
authors.initials: L
authors.lastname: Gendron
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Centre de Recherche du CHU de Sherbrooke, Centre d'excellence en neurosciences de l'Univeristé de Sherbrooke, and Institut de Pharmacologie de Sherbrooke, Sherbrooke, Quebec, Canada (L.G.); Québec Pain Research Network, Sherbrooke, Quebec, Canada (L.G.); Departments of Anesthesiology and Perioperative Care and Pharmacology, University of California, Irvine, California (C.M.C.); Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.M.C.); Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, California (M.v.Z.); Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montréal, Montreal, Quebec, Canada (P.W.S.); and Departments of Psychiatry, Pharmacology, and Neurosciences, Faculty of Medicine, University of Montréal and Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada (G.P.).
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cahill
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Centre de Recherche du CHU de Sherbrooke, Centre d'excellence en neurosciences de l'Univeristé de Sherbrooke, and Institut de Pharmacologie de Sherbrooke, Sherbrooke, Quebec, Canada (L.G.); Québec Pain Research Network, Sherbrooke, Quebec, Canada (L.G.); Departments of Anesthesiology and Perioperative Care and Pharmacology, University of California, Irvine, California (C.M.C.); Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.M.C.); Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, California (M.v.Z.); Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montréal, Montreal, Quebec, Canada (P.W.S.); and Departments of Psychiatry, Pharmacology, and Neurosciences, Faculty of Medicine, University of Montréal and Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada (G.P.).
authors.forename: Mark
authors.initials: M
authors.lastname: von Zastrow
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Centre de Recherche du CHU de Sherbrooke, Centre d'excellence en neurosciences de l'Univeristé de Sherbrooke, and Institut de Pharmacologie de Sherbrooke, Sherbrooke, Quebec, Canada (L.G.); Québec Pain Research Network, Sherbrooke, Quebec, Canada (L.G.); Departments of Anesthesiology and Perioperative Care and Pharmacology, University of California, Irvine, California (C.M.C.); Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.M.C.); Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, California (M.v.Z.); Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montréal, Montreal, Quebec, Canada (P.W.S.); and Departments of Psychiatry, Pharmacology, and Neurosciences, Faculty of Medicine, University of Montréal and Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada (G.P.).
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Centre de Recherche du CHU de Sherbrooke, Centre d'excellence en neurosciences de l'Univeristé de Sherbrooke, and Institut de Pharmacologie de Sherbrooke, Sherbrooke, Quebec, Canada (L.G.); Québec Pain Research Network, Sherbrooke, Quebec, Canada (L.G.); Departments of Anesthesiology and Perioperative Care and Pharmacology, University of California, Irvine, California (C.M.C.); Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.M.C.); Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, California (M.v.Z.); Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montréal, Montreal, Quebec, Canada (P.W.S.); and Departments of Psychiatry, Pharmacology, and Neurosciences, Faculty of Medicine, University of Montréal and Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada (G.P.) graciela.pineyro.filpo@umontreal.ca.
authors.forename: Graciela
authors.initials: G
authors.lastname: Pineyro
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods; D010147:Pain Measurement; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D017465:Receptors, Opioid, delta