In vivo properties of KNT-127, a novel δ opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice.

TitleIn vivo properties of KNT-127, a novel δ opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice.
Publication TypeJournal Article
Year of Publication2014
AuthorsNozaki C, Nagase H, Nemoto T, Matifas A, Kieffer BL, Gaveriaux-Ruff C
JournalBr J Pharmacol
Volume171
Issue23
Pagination5376-86
Date Published2014 Dec
ISSN1476-5381
KeywordsAnalgesics, Animals, Antidepressive Agents, Behavior, Animal, Benzamides, Depression, Drug Tolerance, Freund's Adjuvant, Hot Temperature, Hyperalgesia, Male, Mice, Inbred C57BL, Mice, Knockout, Morphinans, Motor Activity, Pain, Piperazines, Receptors, Opioid, delta
Abstract

BACKGROUND AND PURPOSE: 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.EXPERIMENTAL APPROACH: 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.KEY 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 AND IMPLICATIONS: 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.

DOI10.1111/bph.12852
Alternate JournalBr. J. Pharmacol.
PubMed ID25048778
PubMed Central IDPMC4294046
Grant ListDA05010 / DA / NIDA NIH HHS / United States
P50 DA005010 / DA / NIDA NIH HHS / United States

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