δ-Opioid mechanisms for ADL5747 and ADL5859 effects in mice: Analgesia, locomotion, and receptor internalization

Chihiro Nozaki, Bertrand Le Bourdonnec, David Reiss, Rolf T. Windh, Patrick J. Little, Roland E. Dolle, Brigitte L. Kieffer*, Claire Gavériaux-Ruff

*この研究の対応する著者

研究成果: Article査読

56 被引用数 (Scopus)

抄録

N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4′-piperidine]-4-yl) benzamide (ADL5859) and N,N-diethyl-3-hydroxy-4-(spiro-[chromene-2,4′- piperidine]-4-yl)benzamide (ADL5747) are novel δ-opioid agonists that show good oral bioavailability and analgesic and antidepressive effects in the rat and represent potential drugs for chronic pain treatment. Here, we used genetic approaches to investigate molecular mechanisms underlying their analgesic effects in the mouse. We tested analgesic effects of ADL5859 and ADL5747 in mice by using mechanical sensitivity measures in both complete Freund's adjuvant and sciatic nerve ligation pain models. We examined their analgesic effects in δ-opioid receptor constitutive knockout (KO) mice and mice with a conditional deletion of δ-receptor in peripheral voltage-gated sodium channel (Nav)1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, and the prototypical δ agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethyl-piperazin- 1-yl]-(3-methoxyphenyl)methyl]-N,Ndiethyl-benzamide (SNC80) as a control, significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of all three δ-opioid agonists were abolished in constitutive δ-receptor KO mice and strongly diminished in δ-receptor cKO mice. We also measured two other well described effects of δ agonists, increase in locomotor activity and agonist-induced receptor internalization by using knock-in mice expressing enhanced green fluorescence protein-tagged δ receptors. In contrast to SNC80, ADL5859 and ADL5747 did not induce either hyperlocomotion or receptor internalization in vivo. In conclusion, both ADL5859 and ADL5747 showed efficient pain-reducing properties in the two models of chronic pain. Their effects were mediated by δ-opioid receptors, with a main contribution of receptors expressed on peripheral Nav1.8-positive neurons. The lack of in vivo receptor internalization and locomotor activation, typically induced by SNC80, suggests agonist-biased activity at the receptor for the two drugs.

本文言語English
ページ(範囲)799-807
ページ数9
ジャーナルJournal of Pharmacology and Experimental Therapeutics
342
3
DOI
出版ステータスPublished - 2012 9
外部発表はい

ASJC Scopus subject areas

  • 分子医療
  • 薬理学

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