Studies of μ-, κ-, and δ-Opioid Receptor Density and G Protein Activation in the Cortex and Thalamus of Monkeys

Ko, Mei‐Chuan; Lee, H.; Harrison, Charlotte; Clark, Mary Jo; Song, Hye-Jin; Naughton, Norah N.; Woods, James H.; Traynor, J. R.

doi:10.1124/jpet.103.050625

Cited by 40 publications

(26 citation statements)

References 29 publications

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“…These results are similar to those reported in another study showing that naltrexone displayed 5-fold higher affinity than 6␤-naltrexol for sites labeled by [ 3 H]DAMGO in guinea pig brain homogenate (Nelson et al, 1994). To compare the in vitro antagonist potency of both compounds, [ 35 S]GTP␥S binding was used to provide a functional correlate of ligand-binding experiments (Traynor and Nahorski, 1995;Ko et al, 2003). DAMGO concentrationdependently increased the binding of [ 35 S]GTP␥S over basal by 52% in the monkey thalamus, consistent with previous findings that the MOR is abundant and the maximum of G protein activation by a MOR agonist can be observed in the primate thalamic region (Sim-Selley et al, 1999;Ko et al, 2003).…”

Section: Discussionsupporting

confidence: 86%

“…Both cortical and thalamic membranes of monkeys were prepared according to the procedure described in a previous study (Ko et al, 2003). Cortical membranes (400 g of protein) of monkeys were incubated for 75 min at 25°C with 1 nM [ 3 H]DAMGO and varying concentrations of unlabeled 6␤-naltrexol or naltrexone (0.03-100 nM) in 50 mM Tris buffer, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

“…2). Because [ 3 H]diprenorphine is nonselective, these experiments were performed in homogenates of monkey thalamus, which expresses predominantly -opioid receptors (Ko et al, 2003). Experiments were performed in low-ionic strength 50 mM Tris buffer, pH 7.4, or in 50 mM Tris containing 100 mM NaCl and 10 M GTP␥S to promote a low-agonist affinity state of the receptor.…”

Section: Experimental Designsmentioning

confidence: 99%

“…35 S]GTP␥S binding in the monkey thalamic membranes (Ko et al, 2003). Apparent pA 2 analysis was used to determine the in vivo antagonist potency of 6␤-naltrexol and to be compared with the pA 2 value of naltrexone under similar conditions (Ko et al, 1998).…”

mentioning

confidence: 99%

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Differential in Vivo Potencies of Naltrexone and 6β-Naltrexol in the Monkey

Ko¹,

Divin²,

Lee³

et al. 2005

J Pharmacol Exp Ther

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6␤-Naltrexol is the major metabolite of the opioid receptor antagonist, naltrexone, in humans. However, there are no functional studies of 6␤-naltrexol in primates. The aim of this study was to compare the in vitro and in vivo potencies of naltrexone and 6␤-naltrexol in rhesus monkeys. Affinity and potency were determined using radioligand displacement and stimulation of 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding in monkey brain membranes. In vivo apparent pA 2 analysis was applied to compare the -opioid receptor (MOR) antagonist potency of both compounds in nondependent monkeys. In addition, the potencies of both compounds were determined in precipitating withdrawal manifested by increased respiratory parameters in acute morphine-dependent monkeys. In vitro assays revealed that naltrexone displayed 2-fold higher affinity and potency than 6␤-naltrexol for the MOR binding site and for MOR agonist-stimulated [35 S]GTP␥S binding, respectively. 6␤-Naltrexol (0.32-3.2 mg/kg) dose-dependently produced parallel rightward shifts of the dose-response curve of alfentanil-induced antinociception. Nevertheless, the apparent pA 2 value of 6␤-naltrexol (6.5) was 100-fold less potent than that of naltrexone (8.5) determined previously. 6␤-Naltrexol was also less potent than naltrexone in antagonizing other MOR-mediated effects including respiratory depression and itch/scratching. Naltrexone (0.0032-0.032 mg/kg) and 6␤-naltrexol (0.32-3.2 mg/kg) retained the same potency difference in precipitating withdrawal to a similar degree. Furthermore, 6␤-naltrexol failed to block naltrexone-precipitated withdrawal in morphine-dependent monkeys. These results indicate that naltrexone and 6␤-naltrexol display similar pharmacological actions with a large in vivo potency difference in monkeys such that 6␤-naltrexol may play a minimal role in the therapeutic or antagonist effects of naltrexone in primates.

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Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Experimental Designsmentioning

confidence: 99%

mentioning

confidence: 99%

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Differential in Vivo Potencies of Naltrexone and 6β-Naltrexol in the Monkey

Ko¹,

Divin²,

Lee³

et al. 2005

J Pharmacol Exp Ther

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“…Behavioral and neurochemical studies have shown that SNC80 produces delta receptormediated effects in rhesus monkeys and has high intrinsic efficacy at delta receptors Brandt et al, 2001a;Ko et al, 2003). Previous research has demonstrated that delta opioid receptor agonists produce dose-dependent decreases in food-maintained behavior, and the potency to decrease food-maintained responding correlated with affinity at delta opioid receptors .…”

Section: Discussionmentioning

confidence: 99%

Effects of the selective delta opioid agonist SNC80 on cocaine- and food-maintained responding in rhesus monkeys

Carmo

Mello

Rice

et al. 2006

European Journal of Pharmacology

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Delta agonists such as SNC80 ((+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide) produce some cocaine-like behavioral effects and warrant evaluation as candidate "agonist" medications for cocaine abuse. The present study examined acute and chronic effects of the systemically active delta agonist SNC80 on cocaine-and food-maintained responding in rhesus monkeys. Acute SNC80 (0.32-3.2 mg/kg, i.m.) pretreatment dose-dependently decreased cocaine self-administration (0.0032 mg/kg/injection), but doses of SNC80 that decreased cocaine self-administration also decreased food-maintained responding. In chronic studies, SNC80 (0.32-3.2 mg/kg/h, i.v.) was delivered for 7 days, and food or cocaine (0.01 mg/kg/injection) was available during 4 daily components of food availability and 4 daily components of drug availability. Chronic SNC80 (1.8 mg/kg/h) tended to decrease cocaine self-administration but produced greater reductions in food-maintained responding. A higher dose of 3.2 mg/kg/h SNC80 eliminated both cocaine-and food-maintained responding and produced profound sedation in one monkey and was not tested in other monkeys. These findings indicate that SNC80 produced dose-dependent and nonselective reductions in cocaine self-administration. These results suggest that SNC80 is unlikely to be useful as a treatment for cocaine dependence.

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Mechanisms and treatment of opioid‐induced pruritus: Peripheral and central pathways

Okutani,

Lo Vecchio,

Arendt‐Nielsen

2023

European Journal of Pain

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Background and ObjectivePruritus (also known as itch) is defined as an unpleasant and irritating sensation of the skin that provokes an urge to scratch or rub. It is well known that opioid administration can cause pruritus, which is paradoxical as itch and pain share overlapping sensory pathways. Because opioids inhibit pain but can cause itching. Significant progress has been made to improve our understanding of the fundamental neurobiology of itch; however, much remains unknown about the mechanisms of opioid‐induced pruritus. The prevention and treatment of opioid‐induced pruritus remains a challenge in the field of pain management. The objective of this narrative review is to present and discuss the current body of literature and summarize the current understanding of the mechanisms underlying opioid‐induced pruritus, and its relationship to analgesia, and possible treatment options.ResultsThe incidence of opioid‐induced pruritus differs with different opioids and routes of administration, and the various mechanisms can be broadly divided into peripheral and central. Especially central mechanisms are intricate, even at the level of the spinal dorsal horn. There is evidence that opioid receptor antagonists and mixed agonist and antagonists, especially μ‐opioid antagonists and κ‐opioid agonists, are effective in relieving opioid‐induced pruritus. Various treatments have been used for opioid‐induced pruritus; however, most of them are controversial and have conflicting results.ConclusionThe use of a multimodal analgesic treatment regimen combined with a mixed antagonist and κ agonists, especially μ‐opioid antagonists, and κ‐opioid agonists, seems to be the current best treatment modality for the management of opioid‐induced pruritus and pain.SignificanceOpioids remain the gold standard for the treatment of moderate to severe acute pain as well as cancer pain. It is well known that opioid‐induced pruritus often does not respond to regular antipruritic treatment, thereby posing a challenge to clinicians in the field of pain management. We believe that our review makes a significant contribution to the literature, as studies on the mechanisms of opioid‐induced pruritus and effective management strategies are crucial for the management of these patients.

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Studies of μ-, κ-, and δ-Opioid Receptor Density and G Protein Activation in the Cortex and Thalamus of Monkeys

Abstract: The aim of this study was to investigate the relative density of -, -, and ␦-opioid receptors (MOR, KOR, and DOR) and guanosine 5Ј-O-(3-[

Cited by 40 publications

References 29 publications

Differential in Vivo Potencies of Naltrexone and 6β-Naltrexol in the Monkey

Differential in Vivo Potencies of Naltrexone and 6β-Naltrexol in the Monkey

Effects of the selective delta opioid agonist SNC80 on cocaine- and food-maintained responding in rhesus monkeys

Mechanisms and treatment of opioid‐induced pruritus: Peripheral and central pathways

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