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            -naphthoyl-β-naltrexamine (NNTA), a highly selective and potent activator of μ/κ-opioid heteromers

Yekkirala, Ajay; Lunzer, Mary M.; McCurdy, Christopher R.; Powers, Michael D.; Kalyuzhny, Alexander E.; Roerig, Sandra C.; Portoghese, Philip S.

doi:10.1073/pnas.1016277108

Cited by 63 publications

(85 citation statements)

References 40 publications

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“…Although there is evidence for MOR-KOR heteromers (Wang et al, 2005;Chakrabarti et al, 2010;Yekkirala et al, 2011), we did not observe an effect of nor-BNI on the potency or efficacy of the MOR agonist DAMGO. It was recently shown that expression of MOR-KOR heteromers in spinal cord was very low in male rats but high in females and regulated by female sex hormones (Chakrabarti et al, 2010).…”

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confidence: 59%

Allosteric Interactions between δ and κ Opioid Receptors in Peripheral Sensory Neurons

Berg¹,

Rowan²,

Gupta³

et al. 2011

Mol Pharmacol

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The peripheral ␦ opioid receptor (DOR) is an attractive target for analgesic drug development. There is evidence that DOR can form heteromers with the -opioid receptor (KOR). As drug targets, heteromeric receptors offer an additional level of selectivity and, because of allosteric interactions between protomers, functionality. Here we report that selective KOR antagonists differentially altered the potency and/or efficacy of DOR agonists in primary cultures of adult rat peripheral sensory neurons and in a rat behavioral model of thermal allodynia. In vitro, the KOR antagonist nor-binaltorphimine (nor-BNI) enhanced the potency of [D-Pen enhanced the effect of DPDPE and decreased the effect of SNC80 to inhibit PGE 2 -stimulated thermal allodynia. In contrast to nor-BNI, the KOR antagonist 5Ј-guanidinonaltrindole (5Ј-GNTI) reduced the response of DPDPE both in cultured neurons and in vivo. Evidence for DOR-KOR heteromers in peripheral sensory neurons included coimmunoprecipitation of DOR with KOR, a DOR-KOR heteromer selective antibody augmented the antinociceptive effect of DPDPE in vivo, and the DOR-KOR heteromer agonist 6Ј-GNTI inhibited adenylyl cyclase activity in vitro as well as PGE 2 -stimulated thermal allodynia in vivo. Taken together, these data suggest that DOR-KOR heteromers exist in rat primary sensory neurons and that KOR antagonists can act as modulators of DOR agonist responses most likely through allosteric interactions between the protomers of the DOR-KOR heteromer.

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confidence: 59%

Allosteric Interactions between δ and κ Opioid Receptors in Peripheral Sensory Neurons

Berg¹,

Rowan²,

Gupta³

et al. 2011

Mol Pharmacol

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“…MOR-1 also dimerizes with opioid receptor-like 1 receptors to generate a target with a novel pharmacologic profile (Pan et al, 2002). More recently, an intriguing compound was reported that targets a MOR-1/KOR-1 heterodimer (Yekkirala et al, 2011). N-Naphthoyl-b-naltrexamine is a potent analgesic that lacks physical dependence or reward behavior.…”

Section: Discussionmentioning

confidence: 99%

“…However, they differ in their mechanisms of action. N-Naphthoyl-b-naltrexamine acts through a heterodimer of MOR-1 and KOR-1 while IBNtxA retains full analgesic activity in triple KO mice that lack KOR-1 (Yekkirala et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

Grinnell

Majumdar

Narayan

et al. 2014

J Pharmacol Exp Ther

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IBNtxA (39-iodobenzoyl-6b-naltrexamide) is a potent analgesic in mice lacking many traditional opioid side effects. In mice, it displays no respiratory depression, does not produce physical dependence with chronic administration, and shows no crosstolerance to morphine. It has limited effects on gastrointestinal transit and shows no reward behavior. Biochemical studies indicate its actions are mediated through a set of m-opioid receptor clone MOR-1 splice variants associated with exon 11 that lack exon 1 and contain only six transmembrane domains. Like the mouse and human, rats express exon 11-associated splice variants that also contain only six transmembrane domains, raising the question of whether IBNtxA would have a similar pharmacologic profile in rats. When given systemically, IBNtxA is a potent analgesic in rats, with an ED 50 value of 0.89 mg/kg s.c., approximately 4-fold more potent than morphine. It shows no analgesic cross-tolerance in morphine-pelleted rats. IBNtxA displays no respiratory depression as measured by blood oxygen saturation. In contrast, oximetry shows that an equianalgesic dose of morphine lowers blood oxygen saturation values by 30%. IBNtxA binding is present in a number of brain regions, with the thalamus standing out with very high levels and the cerebellum with low levels. As in mice, IBNtxA is a potent analgesic in rats with a favorable pharmacologic profile and reduced side effects.

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“…Importantly, opioid efficacy in the [Ca 2+ ] i assay has produced similar and consistent results when compared with opioid efficacy in the [ 35 S]GTPγS assay providing a convenient, nonradiological measure of whole cell efficacy. 9,19 SNC80 selectively activated μ−δ heteromer in HEK293 cells with an EC 50 = 52.8 ± 27.8 nM (SEM) (Figure 3), with a mean peak ΔRFU effect of 746 ± 83 (SEM), n = 3 (12). Cells expressing other opioid receptors were substantially less potently activated.…”

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confidence: 98%

The δ Opioid Receptor Agonist SNC80 Selectively Activates Heteromeric μ–δ Opioid Receptors

Metcalf

Yekkirala

Powers

et al. 2012

ACS Chem. Neurosci.

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Coexpressed and colocalized μ-and δ-opioid receptors have been established to exist as heteromers in cultured cells and in vivo. However the biological significance of opioid receptor heteromer activation is less clear. To explore this significance, the efficacy of selective activation of opioid receptors by SNC80 was assessed in vitro in cells singly and coexpressing opioid receptors using a chimeric G-proteinmediated calcium fluorescence assay, SNC80 produced a substantially more robust response in cells expressing μ−δ heteromers than in all other cell lines. Intrathecal SNC80 administration in μ-and δ-opioid receptor knockout mice produced diminished antinociceptive activity compared with wild type. The combined in vivo and in vitro results suggest that SNC80 selectively activates μ−δ heteromers to produce maximal antinociception. These data contrast with the current view that SNC80 selectively activates δ-opioid receptor homomers to produce antinociception. Thus, the data suggest that heteromeric μ−δ receptors should be considered as a target when SNC80 is employed as a pharmacological tool in vivo. KEYWORDS: μ opioid receptor, δ opioid receptor, μ−δ heteromer, SNC80, knockout, antinociception C ompound SNC80 (Figure 1) has been employed as the prototypic nonpeptide, selective δ-opioid receptor agonist for nearly 20 years. The experimental techniques employed to define the δ-selectivity of SNC80 included radioligand binding, smooth muscle assays, and in vivo antagonism studies employing selective δ-antagonists. 1−4 SNC80 has found broad recognition and adoption as a selective δ-agonist standard, occupying the previously vacant nonpeptide selective δ-agonist niche in the opioid pharmacological toolbox. 3 However, in view of the discovery of opioid receptor heteromers as targets for ligands over the past decade, it is possible that opioid receptor heteromers may be activated by SNC80. In this regard, three heteromers, μ−δ, 5 μ−κ, 6 and κ−δ, 7 have been established in heterologous cell lines, 8 and selective ligands that target these heteromers have been identified for each of the above heteromers. 9−11 Moreover, heteromeric μ−δ receptors have been detected using selective antibodies in both cultured cells and DRG neurons. 12 Thus, δ-receptors organized as heteromers could be relevant in the action of SNC80.In this regard, SNC80-treated μ-opioid receptor knockout (μ-KO) mice have been found to be without effect in a visceral antiwrithing test. 13 Also, SNC80 produced an antihyperalgesic effect in WT mice but lacked this effect in μ-KO mice, 14 an effect similar to a separate study in δ-KO mice. 15 Additionally, in vitro studies on the effects of SNC80 on opioid receptors suggested the involvement of μ-opioid receptors on the activity of SNC80. These included the finding that colocalized μ-and δ-opioid receptors in large and small dorsal root ganglion (DRG) neurons 16 are cointernalized into the same subcellular compartment for lysosomal degradation upon treatment with

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N -naphthoyl-β-naltrexamine (NNTA), a highly selective and potent activator of μ/κ-opioid heteromers

Cited by 63 publications

References 40 publications

Allosteric Interactions between δ and κ Opioid Receptors in Peripheral Sensory Neurons

Allosteric Interactions between δ and κ Opioid Receptors in Peripheral Sensory Neurons

Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

The δ Opioid Receptor Agonist SNC80 Selectively Activates Heteromeric μ–δ Opioid Receptors

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