ADL5859 and ADL5747 are novel delta opioid agonists that show good oral bioavailability, analgesic and antidepressive effects in the rat, and represent potential drugs to treat chronic pain. 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 using mechanical sensitivity measures in both Complete Freund's Adjuvant and sciatic nerve ligation pain models. We examined their analgesic effects in delta opioid receptor constitutive knockout (KO) mice as well as in mice with a conditional deletion of delta receptor in peripheral Nav1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, as well as the prototypal delta agonist SNC80 as a control, significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of all three delta opioid agonists were abolished in constitutive delta receptor KO mice, and strongly diminished in delta receptor cKO mice. We also measured two other well-described effects of delta agonists, increase in locomotor activity, and agonist-induced receptor internalization using knock-in mice expressing eGFP-tagged delta receptors. In contrast to SNC80, ADL5859 and ADL5747 induced neither hyperlocomotion nor receptor internalization in vivo. In conclusion, both ADL5859 and ADL5747 show efficient pain-reducing properties in the two models of chronic pain. Their effects are mediated by delta 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.
- Received October 19, 2011.
- Revision received April 25, 2012.
- Accepted April 25, 2012.
- The American Society for Pharmacology and Experimental Therapeutics