δ-Opioid Mechanisms for ADL5747 and ADL5859 Effects in Mice: Analgesia, Locomotion, and Receptor Internalization

Abstract

N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4Ј-piperidine]-4-yl) benzamide (ADL5859) and N,N-diethyl-3-hydroxy-4-(spiro-[chromene-2,4Ј-piperidine]-4-yl)benzamide (ADL5747) are novel ␦-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 ␦-opioid receptor constitutive knockout (KO) mice and mice with a conditional deletion of ␦-receptor in peripheral voltage-gated sodium channel (Nav)1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, and the prototypical ␦ 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 ␦-opioid agonists were abolished in constitutive ␦-receptor KO mice and strongly diminished in ␦-receptor cKO mice. We also measured two other well described effects of ␦ agonists, increase in locomotor activity and agonist-induced receptor internalization by using knock-in mice expressing enhanced green fluorescence protein-tagged ␦ 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 ␦-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.

Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of the Indole Alkaloid Mitragynine, Exhibits Potent Antiallodynic Effect on Neuropathic Pain in Mice

“…Although all three major types of opioid receptors (m, d, and k) are able to mediate analgesia and antinociception, they have different pharmacological activities. Recently, a prominent role of d-opioid receptors in chronic pain such as neuropathic pain and inflammatory pain was reported from studies using mutant animals and selective agonists (Nadal et al, 2006;Nozaki et al, 2012). In a neuropathic pain rat model, d-opioid receptor protein expression was increased compared with a control rat in the dorsal root ganglion (Kabli and Cahill, 2007).…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Although morphine is considered selective for m-opioid receptors, selective agonists of the other three members of the extended opioid receptor family (i.e., d-and k-opioid receptors, and nociceptin receptors) also functionally inhibit Ca V 2.2 channels (Gross and Macdonald, 1987;Moises et al, 1994;Motin et al, 1995;Morikawa et al, 1998;Toselli et al, 1999;Larsson et al, 2000;Yeon et al, 2004;Ruiz-Velasco et al, 2005;Evans et al, 2010). As in the case of m-opioid receptors, their activation induces analgesia in various animal models of pain (King et al, 1997;Darland et al, 1998;Field et al, 1999;Mika et al, 2001;Courteix et al, 2004;Nozaki et al, 2012). Although there are no clinically approved d-opioid-and nociceptin receptor-targeting analgesics, there is at least one k-opioid receptor agonist (pentazocine) that is used in humans as an analgesic.…”

Molecular Pharmacology ofδ-Opioid Receptors

“…Neither compound produced convulsions. A subsequent study revealed that these two compounds were also effective in a neuropathic pain model and, unlike SNC80, did not produce receptor internalization (Nozaki et al, 2012).…”