In vivo properties of KNT-127, a novel δ opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice.
|Title||In vivo properties of KNT-127, a novel δ opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Nozaki C, Nagase H, Nemoto T, Matifas A, Kieffer BL, Gaveriaux-Ruff C|
|Journal||Br J Pharmacol|
|Date Published||2014 Dec|
|Keywords||Analgesics, 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|
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.
|Alternate Journal||Br. J. Pharmacol.|
|PubMed Central ID||PMC4294046|
|Grant List||DA05010 / DA / NIDA NIH HHS / United States |
P50 DA005010 / DA / NIDA NIH HHS / United States