Decrease in μ-opioid receptor binding capacity in rat brain after chronic PL017 treatment

Tao, Pao‐Luh; Lee, Haw Yen; Chang, Li-Chien; Loh, Horace H.

doi:10.1016/0006-8993(90)91231-5

Cited by 66 publications

(49 citation statements)

References 14 publications

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“…Likewise, acute etorphine [intrinsic efficacy Ͼ Ͼ morphine (Duttaroy and Yoburn, 1995)] treatment had no effect on ex vivo binding of [ 3 H]diprenorphine to rat brain membranes. In the continued presence of etorphine, an ϳ68% decrease in [ 3 H]diprenorphine binding was observed after chronic, 3-day exposure (Tao et al, 1987). This is consistent with receptor down-regulation following internalization/endocytosis (Keith et al, 1996).…”

Section: Discussionsupporting

confidence: 74%

“…Although diprenorphine is quoted as having a similar in vitro affinity for each subtype (Pfeiffer and Herz, 1982), early in vivo binding studies in rat reported a ϳ4-fold higher affinity of diprenorphine for -relative to ␦-receptor sites (Richards and Sadée, 1985). This suggests that, despite approximately equal numbers of the receptor subtypes in rat cortex, the in vivo signal (a measure of "receptor number/apparent affinity") will predominantly reflect binding to the -receptors, and the signal in the striatum will have similar contributions from -and ␦-receptor sites, despite the 3:7 distribution in favor of the latter (Tao et al, 1987). Thus, detecting subtle subtype differences in occupancy, such as, for example, comparing regional effects of the putative -receptor agonist, oxycodone compared with the -receptor agonist, morphine, could prove difficult.…”

Section: Sensitivity Of [mentioning

confidence: 99%

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Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Hume¹,

Lingford‐Hughes²,

Nataf³

et al. 2007

J Pharmacol Exp Ther

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Previously, we reported minimal opioid receptor occupancy following a clinical dose of the -opioid agonist, methadone, measured in vivo using positron emission tomography (PET) with [11 C]diprenorphine and subsequently used rats to obtain experimental data in support of a high receptor reserve hypothesis (Melichar et al., 2005). Here, we report on further preclinical studies investigating opioid receptor occupancy with oxycodone (-and -receptor agonist), morphine (-receptor agonist), and buprenorphine (partial agonist at the -receptor and antagonist at the ␦-and -receptors), each given at antinociceptive doses. In vivo binding of [ 11 C]diprenorphine was not significantly reduced after treatment with the full agonists but was reduced by ϳ90% by buprenorphine. In addition, given that [ 11 C]diprenorphine is a non-subtype-specific PET tracer, there was no regional variation that might feasibly be interpreted as due to differences in opioid subtype distribution. The data support minimal competition between the high-efficacy agonists and the non-subtype-selective antagonist radioligand and highlight the limitations of [ 11 C]diprenorphine PET to monitor in vivo occupancy. Alternative means may be needed to address clinical issues regarding opioid receptor occupancy that are required to optimize treatment strategies.Positron emission tomography (PET) with the radioligand, [ 11 C]diprenorphine has been used for over a decade to assess or measure opioid receptor function in human brain. Specific binding of this ligand in vivo can be blocked by the opioid receptor antagonist, naloxone (13 g/kg naloxone resulted in ϳ50% reduction in binding; Melichar et al., 2003) and is locally reduced in conditions expected to result in an increased concentration of endogenous agonist; for example, pain (for review, see Sprenger et al., 2005). We had therefore used PET with [ 11 C]diprenorphine to quantify opioid receptor occupancy in methadone-maintained opiate-dependent patients. Our aim was to address clinical issues in treatment of opioid dependence such as agonist dose-to-outcome, with a view to optimizing treatment strategies but, in the end, found no statistically significant reduction in specific binding compared with control (Melichar et al., 2005). A likely explanation was that clinically relevant doses (18 -90 mg daily) of methadone result in low levels of occupancy of opioid receptors. Other factors considered were receptor trafficking, agonist concentration at the site of action, and, since the predominant form of the opioid receptor in vivo is a low agonist affinity state, the limited ability of agonists to block highaffinity binding of an antagonist radiotracer.

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Section: Discussionsupporting

confidence: 74%

Section: Sensitivity Of [mentioning

confidence: 99%

Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Hume¹,

Lingford‐Hughes²,

Nataf³

et al. 2007

J Pharmacol Exp Ther

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“…In previous studies, down-regulation of opioid receptors is produced only by high doses of nonselective and more potent agonists (etorphine, [D-Ala 2 ,D-Leu 5 ]enkephalin) that are associated with significant mortality (22,23,39,40). Although studies have attempted to demonstrate the ability of morphine and several -selective agonists (e.g., fentanyl, PL017, sufentanyl, alfentanyl) to down-regulate opioid receptors (26,41), the magnitude of reduction is either small or not observed.…”

Section: Opioid Receptors In Sensory Neuronsmentioning

confidence: 99%

“…In various brain regions, the up-regulation of opioid receptors by antagonists has been observed (17,18), whereas the effects of chronic exposure to agonist are equivocal. Down-regulation of opioid receptors in brain is observed only after exposure to nonselective agonists (22,23), whereas selective opioid agonists produced either no change (24,25) or an increase in the number of receptors (26) Opioid peptides (DAMGO and DPDPE) were from Peninsula Laboratories (Belmont, CA). Routinely used chemicals were from Sigma Chemical (St. Louis, MO).…”

mentioning

confidence: 99%

Regulation of Opioid Receptors in Rat Sensory Neurons in Culture

1997

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SUMMARYTo determine whether opioid receptors in sensory neurons are regulated by chronic exposure to opioids, we assessed the binding of various opioid ligands to membranes derived from isolated rat dorsal root ganglia neurons grown in culture. ]diprenorphine binding sites, respectively. Preexposure of neurons to 10 M naloxone for 48 hr up-regulated the receptors by 40%, whereas incubation with 100 nM to 10 M DAMGO for 48 hr resulted in a significant decrease in the B max value of opioid receptors, with a maximum reduction of 70%. The identification of a high level of opioid receptors expressed in isolated sensory neurons and their modulation by opioids demonstrates that cultured sensory neurons are an excellent model with which to study opioid receptor regulation.

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“…Presumably there is no increase in receptor number in low calcium, more probably, there is a change in receptor-effector coupling or in the ability of the agonistreceptor complex to transduce the measured effect. Changes in the opioid receptor system of tolerant animals have been controversial although a decrease in the fraction of spare opioid receptors (Chavkin & Goldstein, 1982), in the opioid receptor density (Rogers & El-Fakahany, 1986;Tao et al, 1987) or in receptor-effector coupling (Werling et al, 1989) have been reported. If a functional down-regulation of receptors occurs during opioid tolerance development, agents with low efficacy (i.e.…”

Section: Discussionmentioning

confidence: 99%

Production of antinociception by peripheral administration of [Lys⁷]dermorphin, a naturally occurring peptide with high affinity for μ‐opioid receptors

Negri¹,

Lattanzi²,

Melchiorri³

1995

British J Pharmacology

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Decrease in μ-opioid receptor binding capacity in rat brain after chronic PL017 treatment

Cited by 66 publications

References 14 publications

Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Regulation of Opioid Receptors in Rat Sensory Neurons in Culture

Production of antinociception by peripheral administration of [Lys⁷]dermorphin, a naturally occurring peptide with high affinity for μ‐opioid receptors

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Decrease in μ-opioid receptor binding capacity in rat brain after chronic PL017 treatment

Cited by 66 publications

References 14 publications

Low Sensitivity of the Positron Emission Tomography Ligand [11C]Diprenorphine to Agonist Opiates

Low Sensitivity of the Positron Emission Tomography Ligand [11C]Diprenorphine to Agonist Opiates

Regulation of Opioid Receptors in Rat Sensory Neurons in Culture

Production of antinociception by peripheral administration of [Lys7]dermorphin, a naturally occurring peptide with high affinity for μ‐opioid receptors

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Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Production of antinociception by peripheral administration of [Lys⁷]dermorphin, a naturally occurring peptide with high affinity for μ‐opioid receptors