<i>In vivo</i> profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile

Kuo, Andy; Wyse, Bruce D.; Meutermans, Wim; Smith, Maree T.

doi:10.1111/bph.12696

Cited by 62 publications

(71 citation statements)

References 67 publications

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“…86,87 However, buprenorphine, a clinically important drug with an extreme G protein bias on par with TRV130 produces significant respiratory depression and constipation both in rodent models and humans, suggesting that G protein bias per se is not sufficient to reduce these side effects. 88 Instead, the high intrinsic efficacy of TRV130 for G protein signaling compared to morphine and buprenorphine and the consequent lower receptor occupancy necessary for pain control with TRV-130 could explain its reduced side effects. In fact, there is clear evidence that at least some of the effects of opioids, on respiration are mediated by activity from the G protein.…”

Section: Resultsmentioning

confidence: 99%

Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins

Johnson

Milan‐Lobo

Che

et al. 2016

ACS Chem. Neurosci.

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Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin (2), Vicodin (3), and Dilaudid (4) are “biased” agonists at the μ opioid receptor (OR), wherein they engage G protein signaling but poorly engage β-arrestin and the endocytic machinery. In contrast, endorphins, the endogenous peptide agonists for ORs, are potent analgesics, show reduced liability for tolerance and dependence, and engage both G protein and β-arrestin pathways as “balanced” agonists. We set out to determine if marine-derived alkaloids could serve as novel OR agonist chemotypes with a signaling profile distinct from morphine and more similar to the endorphins. Screening of 96 sponge-derived extracts followed by LC-MS-based purification to pinpoint the active compounds and subsequent evaluation of a mini library of related alkaloids identified two structural classes that modulate the ORs. These included the following: aaptamine (10), 9-demethyl aaptamine (11), demethyl (oxy)–aaptamine (12) with activity at the δ-OR (EC50: 5.1, 4.1, 2.3 μM, respectively) and fascaplysin (17), and 10-bromo fascaplysin (18) with activity at the μ-OR (EC50: 6.3, 4.2 μM respectively). An in vivo evaluation of 10 using δ-KO mice indicated its previously reported antidepressant-like effects are dependent on the δ-OR. Importantly, 17 functioned as a balanced agonist promoting both G protein signaling and β-arrestin recruitment along with receptor endocytosis similar to the endorphins. Collectively these results demonstrate the burgeoning potential for marine natural products to serve as novel lead compounds for therapeutic targets in neuroscience research.

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Section: Resultsmentioning

confidence: 99%

Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins

Johnson

Milan‐Lobo

Che

et al. 2016

ACS Chem. Neurosci.

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“…and/or i.t. route show different pharmacological profiles [6,20]. The Gi/o-protein activates GIRK channels, while Gq-protein-dependent phospholipase C/phosphatidylinositol 4,5-diphosphate (PIP2) signaling inhibits GIRK1 channel activation [21].…”

Section: Discussionmentioning

confidence: 99%

“…Although these MOR agonists show potent analgesic effects against various types of pain [1,2], they have different analgesic profiles in clinical settings [3]. Consistent with this, MOR agonists have interesting antinociceptive differences in several pain model rodents [4][5][6]. Therefore, it is important to understand pharmacological profiles of those for the appropriate use.…”

Section: Introductionmentioning

confidence: 99%

Morphine and oxycodone, but not fentanyl, exhibit antinociceptive effects mediated by G-protein inwardly rectifying potassium (GIRK) channels in an oxaliplatin-induced neuropathy rat model

Kanbara

Nakamura

Shibasaki

et al. 2014

Neuroscience Letters

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“…In contrast to many opioid‐related side‐effects, tolerance does not develop to constipation and so the quality of life of patients is often impaired without proactive management . Although tolerance to respiratory depression usually develops after chronic treatment, its potential lethality in opioid‐naïve patients is the most feared by clinicians …”

Section: Introductionmentioning

confidence: 99%

“…Using this approach, we minimised all controllable parameters in a typical research laboratory. Hence, we have addressed this knowledge gap by comparing our previous data generated in male Sprague Dawley (SD) rats from breeding colony 1 (BC1) with our new data generated using rats from breeding colony 2 (BC2) sourced from a different colony at The University of Queensland. Four opioids, namely, morphine, buprenorphine, DPDPE and U69,593 were administered by ICV injection via a surgically implanted guide cannula, effectively bypassing systemic metabolism, thereby enabling the centrally mediated effects to be quantified .…”

Section: Introductionmentioning

confidence: 99%

In vivo profiling of four centrally administered opioids for antinociception, constipation and respiratory depression: Between‐colony differences in Sprague Dawley rats

Kuo

Smith

2018

Clin Exp Pharma Physio

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Outbred rodent stocks including Sprague Dawley rats, are known for their genetic diversity and so they are often used to develop animal models of human disease. Although between-colony differences in pharmaco-behavioural studies have been published previously, a direct head-to-head comparison study, whereby all research was performed in the same laboratory by the same experimenter utilising the supraspinal route of drug administration in the same strain of rat, is lacking. Herein, we report our head-to-head comparison study, involving assessment of antinociception, constipation and respiratory depression evoked by single bolus intracerebroventricular (ICV) doses of morphine, buprenorphine, DPDPE and U69,593 using male Sprague Dawley rats sourced from a different breeding colony (BC2) from that (BC1) used by us previously. Our data show that there are marked differences in the potency rank order for morphine and buprenorphine between rats sourced from BC2 and BC1. Although ICV morphine evoked a bell-shaped dose-response curve in the constipation test for rats from both colonies, this occurred at higher doses for rats from BC2. In conclusion, our head-to-head comparison shows considerable between-colony differences for the same rat strain, in the potency rank order of two clinically important strong opioid analgesics given by the ICV route.

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In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile

Abstract: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Cited by 62 publications

References 67 publications

Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins

Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins

Morphine and oxycodone, but not fentanyl, exhibit antinociceptive effects mediated by G-protein inwardly rectifying potassium (GIRK) channels in an oxaliplatin-induced neuropathy rat model

In vivo profiling of four centrally administered opioids for antinociception, constipation and respiratory depression: Between‐colony differences in Sprague Dawley rats

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