Selective δ opioid receptor agonists for inflammatory and neuropathic pain

Dondio, Giulio; Ronzoni, Silvano; Farina, Carlo; Graziani, Davide; Parini, Carlo; Petrillo, Paola; Giardina, Giuseppe

doi:10.1016/s0014-827x(01)01020-5

Cited by 31 publications

(19 citation statements)

References 8 publications

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“…The results may reflect differences in receptor activity profiles and suggest that a mixed DOR/MOR profile may offer a decreased propensity to produce tolerance/physical dependence compared with MOR-selective agonists. This is in line with previous studies demonstrating lower tolerance/dependence liabilities associated with DOR versus MOR agonists (Dondio et al, 2001;Codd et al, 2009). It may also reflect potential synergy of DOR/MOR effects for antinociception versus additivity/ subadditivity with respect to mechanisms that drive development of tolerance/dependence (e.g., less occupancy of DOR and MOR populations needed to produce full antinociceptive effects) (Rozenfeld et al, 2007).…”

Section: Discussionsupporting

confidence: 90%

“…For example, the relative contributions of peripheral versus central MORs, and the role that DORs play in modulating respiration, remain unclear and controversial (Pattinson, 2008). There is evidence that DOR selective agonists stimulate (or at least produce less inhibition of) respiration, and DOR agonists can reverse MOR-induced respiratory depression (Su et al, 1998;Dondio et al, 2001). Changes in motor activity in response to opioid administration can affect respiratory measures, including minute ventilation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

In Vivo Characterization of MMP-2200, a Mixed δ/μ Opioid Agonist, in Mice

Lowery

Raymond²,

Giuvelis³

et al. 2010

J Pharmacol Exp Ther

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

In Vivo Characterization of MMP-2200, a Mixed δ/μ Opioid Agonist, in Mice

Lowery

Raymond²,

Giuvelis³

et al. 2010

J Pharmacol Exp Ther

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“…iv Rubiscolin, a bioactive hexapeptide derived from spinach rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase), 166 improves learning (specifically memory consolidation) at doses less than antinociceptive doses 126 and has been reported to be anxiolytic 167 and orexigenic. 168 v SB-235863, a non-peptide selective DOR agonist based on the pirrolomorphinan framework, 169 displays antinociceptive 170 and antihyperalgesic 53 properties. vi SIOM is a non-peptide selective DOR agonist 171 that was used to construct DOR binding models 172 using the messageaddress concept.…”

Section: Azd2327mentioning

confidence: 99%

Delta opioid agonists: a concise update on potential therapeutic applications

Peppin

Raffa

2015

J Clin Pharm Ther

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SUMMARYWhat is known and objective: The endogenous opioid system co-evolved with chemical defences, or at times symbiotic relationships, between plants and other autotrophs and heterotrophic predators -thus, it is not surprising that endogenous opioid ligands and exogenous mimetic ligands produce diverse physiological effects. Among the endogenous opioid peptides (endomorphins, enkephalins, dynorphins and nociception/orphanin FQ) derived from the precursors encoded by four genes (PNOC, PENK, PDYN and POMC) are the pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-PheLeu). The physiological effects of the enkephalins are mediated via 7-transmembrane G protein-coupled receptors, including delta opioid receptor (DOR). We present a concise update on the status of progress and opportunities of this approach. Methods: A literature search of the PUBMED database and a combination of keywords including delta opioid receptor, analgesia, mood and individual compounds identified therein, from industry and other source, and from www.clinicaltrials.com. Results and discussion: DOR agonist and antagonist ligands have been developed with ever increasing affinity and selectivity for DOR over other opioid receptor subtypes and studied for therapeutic utility, primarily for pain relief, but also for other clinical endpoints. What is new and conclusion: Selective DOR agonists have been designed with a large increase in therapeutic window for a variety of potential CNS applications including pain, depression, and learning and memory among others. WHAT IS KNOWN AND OBJECTIVE

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“…The development of several selective nonpeptidic ␦-opioid agonists with small molecular weights and the analysis of novel mouse lines with selected mutations targeting the ␦-opioid receptor have clarified the role of ␦ receptors in pain control and mood disorders Pradhan et al, 2011). In brief, pharmacological data in rodents have demonstrated that ␦-opioid agonists weakly influence acute pain perception (Gallantine and Meert, 2005), but efficiently decrease persistent pain, including inflammatory pain (Fraser et al, 2000;Brandt et al, 2001;Dondio et al, 2001), cancer (Brainin-Mattos et al, 2006;Otis et al, 2011), and neuropathic pain (Dondio et al, 2001;Holdridge and Cahill, 2007;Kabli and Cahill, 2007). The analysis of conventional knockout (KO) mice showed the existence of an endogenous ␦-opioid receptor tone, which reduces chronic pain (Nadal et al, 2006;Gavériaux-Ruff et al, 2008) and improves mood (Filliol et al, 2000;Gavériaux-Ruff and Kieffer, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

Nozaki

Bourdonnec

Reiss

et al. 2012

J Pharmacol Exp Ther

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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.

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Selective δ opioid receptor agonists for inflammatory and neuropathic pain

Cited by 31 publications

References 8 publications

In Vivo Characterization of MMP-2200, a Mixed δ/μ Opioid Agonist, in Mice

In Vivo Characterization of MMP-2200, a Mixed δ/μ Opioid Agonist, in Mice

Delta opioid agonists: a concise update on potential therapeutic applications

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

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