Neuropathic pain is enhanced in δ‐opioid receptor knockout mice

(E)-Methyl 2-((2S,3S,7aS,12bS)-3-ethyl-7a-hydroxy-8-methoxy-1, 2,3,4,6,7,7a,12b-octahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (7-hydroxymitragynine), a main active constituent of the traditional herbal medicine Mitragyna speciosa, is an indole alkaloid that is structurally different from morphine. 7-Hydroxymitragynine induces a potent antinociceptive effect on mouse acute pain through m-opioid receptors. In this study, we developed dual-acting m-and d-opioid agonists MGM-15 and MGM-16 from 7-hydroxymitragynine for the treatment of acute and chronic pain. MGM-16 showed a higher potency than that of 7-hydroxymitragynine and MGM-15 in in vitro and in vivo assays. MGM-16 exhibited a high affinity for m-and d-opioid receptors, with K i values of 2.1 and 7.0 nM, respectively. MGM-16 showed m-and d-opioid full agonistic effects in a guanosine 59-O-(3-[ 35 S]thiotriphosphate) binding assay and in a functional test using electrically elicited guinea pig ileum and mouse vas deferens contractions. Systemic administration of MGM-16 produced antinociceptive effects in a mouse acute pain model and antiallodynic effects in a chronic pain model. The antinociceptive effect of MGM-16 was approximately 240 times more potent than that of morphine in a mouse tail-flick test, and its antiallodynic effect was approximately 100 times more potent than that of gabapentin in partial sciatic nerve-ligated mice, especially with oral administration. The antinociceptive effect of MGM-16 was completely and partially blocked by the m-selective antagonist b-funaltrexamine hydrochloride (b-FNA) and by the d-selective antagonist naltrindole, respectively, in a tail-flick test. The antiallodynic effect of MGM-16 was completely blocked by b-FNA and naltrindole in a neuropathic pain model. These findings suggest that MGM-16 could become a class of a compound with potential therapeutic utility for treating neuropathic pain.

Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 92%

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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

Matsumoto

Narita

Muramatsu

et al. 2013

“…DOP ligands lack side effects often associated with MOP activation in vivo, including antinociceptive tolerance, physical dependence, and self-administration (Negus et al, 1998). DOP knockout mice show enhanced behavioral responses to inflammation and neuropathic injury (Nadal et al, 2006;Gavériaux-Ruff et al, 2008). Interactions between MOP/DOP have been reported and indicate that both activation and blockade of the DOP can improve analgesia and attenuate morphine-induced tolerance (Gendron et al, 2007;Dietis et al, 2009;Schramm and Honda, 2010).…”

Section: Introductionmentioning

confidence: 99%

Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

Largent-Milnes

Brookshire

Skinner

et al. 2013

The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK 1 ) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK 1 antagonist compound [Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF 3 ) 2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain.

“…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). Further analysis of pain responses and ␦-opioid analgesia in conditional KO (cKO) animals has highlighted a critical role of peripheral receptors in chronic pain control .…”

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

Self Cite

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.