title: In vivo properties of KNT-127, a novel δ opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice.
abstract: OBJECTIVE
  Activation of δ opioid (DOP) receptors regulates pain and emotional responses, and also displays ligand-biased agonism. KNT-127 (1,2,3,4,4a,5,12,12a-octahydro-2-methyl-4aβ,1β-([1,2]benzenomethano)-2,6-diazanaphthacene-12aβ,17-diol) is a novel DOP receptor agonist inducing analgesia and antidepressant effects in mice. Here, we have assessed KNT-127 for (i) analgesia against chronic inflammatory pain; (ii) effects on depression, locomotion and DOP receptor internalization; and (iii) for cross-tolerance to analgesic and antidepressant effects of acute treatment by other DOP receptor agonists.
  
  
  METHODS
  Inflammatory pain was induced by complete Freund's adjuvant injection into tail or hindpaw, and thermal and mechanical sensitivities were determined in mice. Locomotor and antidepressant-like effects were measured using actimetry and forced swim test respectively. In vivo KNT-127 selectivity and internalization were assessed using DOP receptor knockout mice and knock-in mice expressing fluorescent-tagged DOP receptors. KNT-127 was injected acutely at 0.1-10.0 mg·kg(-1) or administered chronically at 5 mg·kg(-1) daily over 5 days.
  
  
  RESULTS
  Acute treatment with KNT-127 reversed inflammatory hyperalgesia, produced an antidepressant-like effect but induced neither hyperlocomotion nor receptor sequestration. Chronic treatment with KNT-127 induced tolerance and cross-tolerance to SNC80-induced analgesia, but no tolerance to SNC80-evoked hyperlocomotor or antidepressant-like effects.
  
  
  CONCLUSIONS
  The DOP receptor agonist KNT-127 induced agonist-specific acute and chronic responses, at both behavioural and cellular levels. It displays activities similar to the other recently reported DOP agonists, AR-M1000390, ADL5747 and ADL5859, and differs from SNC80. SNC80 differs from the other DOP receptor agonists including KNT-127, by exhibiting ligand-biased tolerance at this receptor.
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Strasbourg, France.
authors.forename: C
authors.initials: C
authors.lastname: Nozaki
authors.forename: H
authors.initials: H
authors.lastname: Nagase
authors.forename: T
authors.initials: T
authors.lastname: Nemoto
authors.forename: A
authors.initials: A
authors.lastname: Matifas
authors.forename: B L
authors.initials: BL
authors.lastname: Kieffer
authors.forename: C
authors.initials: C
authors.lastname: Gaveriaux-Ruff
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy*; D004361:Drug Tolerance; D005620:Freund's Adjuvant; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009019:Morphinans / Q000494:pharmacology / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010879:Piperazines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D001549:Benzamides; C555233:KNT 127; D009019:Morphinans; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D005620:Freund's Adjuvant