Antinociceptive profile of salvinorin A, a structurally unique kappa opioid receptor agonist

McCurdy, Christopher R.; Sufka, Kenneth J.; Smith, Grant H.; Warnick, Jason E.; Nieto, Marcelo J.

doi:10.1016/j.pbb.2005.12.011

Cited by 121 publications

(113 citation statements)

References 22 publications

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“…Behavioral studies report that Sal A exhibits antinociceptive activity (26), is aversive in rodents (24), dose-dependently increases immobility in the forced swim test (27), is anxiolytic in the elevated plus maze test (28), and can attenuate cocaineinduced drug seeking behavior (29). In this study, we find that Colly, like Sal A, exhibits antinociception and is aversive in mice.…”

Section: Discussionsupporting

confidence: 57%

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Gupta

Gomes

Bobeck

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10-to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non-histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects.G-protein-coupled receptors | natural compounds | salvinorin A | dynorphin | antinociception

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Section: Discussionsupporting

confidence: 57%

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Gupta

Gomes

Bobeck

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…S2 and S3). Salvinorin A is a highly selective kappa ligand (13,14). Like U50,488H, its analgesic response was lost in E11 KO mice (Table 1 and SI Appendix, Fig.…”

Section: Significancementioning

confidence: 99%

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Marrone

Grinnell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α 2 -adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α 2 -mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa 1 , and α 2 actions from analgesia.GPCR | truncation | analgesia | mu opioid receptor | morphine M odulation of pain is complex, with contributions from a variety of neurotransmitter systems. The opioid systems are particularly prominent clinically because of the availability of many potent and effective drugs, particularly those acting through mu opioid receptors. The mu opioid receptor gene, Oprm1, is complex, containing two independent promoters that generate dozens of variants through both 5′ and 3′ alternative splicing patterns that are highly conserved among multiple species (SI Appendix, Fig. S1) (1). Like the first mu opioid receptor (Oprm1) clone, MOR-1, most of the variants are traditional seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs) generated from the exon 1 (E1) promoter. Each contains exons 1, 2, and 3, differing only at the intracellular C terminus due to 3′ splicing. The exon 11 (E11) promoter, located ∼30 kb upstream of exon 1, generates a set of truncated proteins lacking the first transmembrane domain because of the absence of exon 1, resulting in only six transmembrane domains (6TM).Classically, opioid mechanisms were defined pharmacologically by using selective agonists and antagonists, but genetic approaches offer a more precise approach toward assessing the pharmacological contributions of the various Oprm1 splice variants. Mice have been developed that have the selective loss of only 6TM variants (E11 KO) (2), only the exon 1-containing 7TM and 1TM variants (E1 KO) (3) or the loss of all Oprm1 variants (E1/E11 KO) (4) (SI Appendix, Fig. S1). These models provide insights into the differing pharmacology of the full-length 7TM and the truncated 6TM variants. Full-length 7TM variants are essential for morphine actions (3, 5-7). However, m...

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“…Curiosamente, diferente de outras substâncias alucinógenas clássicas, o alvo molecular responsável por sua ação não são os receptores serotoninérgicos 5-HT 2A . Estudos in vitro e in vivo indicaram que salvinorina A é um agonista pleno dos receptores opióides κ, responsável pelos efeitos analgésico e psicotomimético (Sheffler & Roth, 2003;Yan & Roth, 2004;Prisinzano, 2005;John et al, 2006;McCurdy et al, 2006).…”

Section: Salvinorina Aunclassified

Terpenóides com atividade sobre o Sistema Nervoso Central (SNC)

Passos¹,

Arbo²,

Rates³

et al. 2009

Rev. bras. farmacogn.

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RESUMO:Os terpenóides constituem um vasto grupo de metabólitos secundários com ações sobre o SNC, destacando-se suas atividades sedativa, ansiolítica, antinociceptiva, anticonvulsivante, pró-convulsivante e alucinógena. Neste trabalho foi realizada uma revisão bibliográfica sobre terpenóides com ações descritas no SNC, enfocando moléculas e sistemas neurotransmissores relacionados com sua atividade. As substâncias abordadas encontram-se divididas em mono, sesqui, di, tri e meroterpenóides e incluem compostos isolados e plantas que apresentam ação principalmente sobre os sistemas neurotransmissores GABAérgico, glutamatérgico, dopaminérgico e opióide.Unitermos: Terpenóides, sistema nervoso central, neurotransmissores.ABSTRACT: "Terpenoids with activity in the Central Nervous System (CNS)". The terpenoids are a large group of secondary metabolites which display many activities in the CNS, such as sedative, ansiolytic, antinociceptive, anticonvulsant, pro-convulsant and hallucinogenic. In this work we performed a research on terpenoids that exert effects on the CNS, focusing molecules and neurotransmitter systems related to their actions. The substances approached were classified as mono, sesqui, di, tri and meroterpenoids and include isolated compounds and plants which exert activities mainly on GABAergic, glutamatergic, dopaminergic and opioid neurotransmitter systems.

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Antinociceptive profile of salvinorin A, a structurally unique kappa opioid receptor agonist

Cited by 121 publications

References 22 publications

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Terpenóides com atividade sobre o Sistema Nervoso Central (SNC)

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