Differential up-regulation of microsomal and synaptic membrane μ opioid receptors

Moudy, Anna M.; Spain, James; Coscia, Carmine J.

doi:10.1016/0006-291x(85)91194-5

Cited by 14 publications

(13 citation statements)

References 11 publications

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“…Comparable B MAX values were measured in control SPM and MI membranes (Fig. 2) that are consistent with earlier reports (Moudy et al, 1985). -Sites were up-regulated by 68% in MI upon 5 days of morphine exposure.…”

Section: Discussionsupporting

confidence: 91%

“…Sternini et al (1996) showed that morphine partially inhibited the etorphine-induced -opioid receptor rapid endocytosis in neurons. It is well documented that chronic administration of opioid receptor antagonists produce up-regulation of surface -sites and their increased G protein coupling (Moudy et al, 1985;Belcheva et al, 1991). However, it should be noted that in our experiments, only the intracellular sites were affected by shorter morphine exposure but not those in the SPM (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…We prepared membrane fractions originating from the cell surface (SPM) and from "light vesicles" or microsomes (MI) that are enriched in endoplasmic reticulum, Golgi membranes, and endosomes. They have been previously subjected to a detailed characterization by marker enzymes, electron microscopy, and receptor binding experiments (Roth et al, 1981;Moudy et al, 1985;Szü cs and Coscia, 1992). The availability of these membrane fractions allowed us to study the subcellular distribution of -opioid receptors and their cognate G proteins in morphine-tolerant rat brain.…”

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confidence: 99%

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Chronic Morphine-Induced Changes in μ-Opioid Receptors and G Proteins of Different Subcellular Loci in Rat Brain

Fábián¹,

Bozó²,

Szikszay³

et al. 2002

J Pharmacol Exp Ther

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Prolonged exposure to opioid agonists can induce adaptive changes resulting in tolerance and dependence. Here, rats were rendered tolerant by subcutaneous injections of increasing doses of morphine from 10 to 60 mg/kg for 3, 5, or 10 consecutive days. -ol]-enkephalin). Although the density of surface -sites did not change after the 5-day morphine treatment, up-regulation of synaptic plasma membrane binding was detected after the 10-day drug administration. In contrast, the number of -binding sites in a light vesicle or microsomal fraction (MI) was elevated by 68 and 30% after 5 and 10 days of morphine exposure, respectively. The up-regulated MI -sites displayed enhanced coupling to G proteins compared with those detected in saline-treated controls. Pertussis toxin catalyzed ADP ribosylation, and Western blotting with specific antisera was used to quantitate chronic morphine-induced changes in levels of various G protein ␣-subunits. Morphine treatment of 5 days and longer induced significant increases in levels of G␣ o , G␣ i1 , and G␣ i2 in MI fractions that are part of an adaptation process. Up-regulation of intracellular -sites may be the result of post-translational changes and in part de novo synthesis. The results provide the first evidence that distinct regulation of intracellular -opioid receptor G protein coupling and G protein levels may accompany the development of morphine tolerance.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Chronic Morphine-Induced Changes in μ-Opioid Receptors and G Proteins of Different Subcellular Loci in Rat Brain

Fábián¹,

Bozó²,

Szikszay³

et al. 2002

J Pharmacol Exp Ther

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“…Chronic in vivo or in vitro administration of opioid antagonists such as naloxone and naltrexone has been shown to result in p-opioid receptor upregulation within whole homogenates [14,16,18,[30][31][32] or selective limbic regions [15,17,33] of the rat brain. In addition, it was shown that treatment with these antagonists in creased the total number of p-opioid receptors (Bmax) as opposed to changing their affinity (Ku) [14,[16][17][18][29][30][31]. Increases in p-opioid receptor binding were found to be twofold greater in microsomes than in synaptic mem brane fractions [14], indicating that part of the newly ex pressed opioid-binding sites may be intracellular.…”

Section: Discussionmentioning

confidence: 99%

“…The validity of this hypothesis is predicated on the notion that opioid target neurons in the MPOA respond to a reduced [3-endorphin input by upregulating p-receptors. This pos sibility appears likely given that u-opioid upregulatory re sponses to diminished ligand availability have been dem onstrated in other brain regions [14][15][16][17][18], Nevertheless, it remains to be determined whether such a mechanism ap plies to the MPOA, especially since in the EV model, loss of |3-endorphin neurons and upregulation of p-opioid re ceptors may be caused independently by unrelated ac tions of estradiol.…”

mentioning

confidence: 99%

Monosodium Glutamate-lnduced Reductions in Hypothalamic Beta-Endorphin Content Result in Mu-Opioid Receptor Upregulation in the Medial Preoptic Area

Desjardins

Brawer²,

Beaudet³

1992

Neuroendocrinology

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Estradiol valerate (EV) treatment in the rat induces a lesion of the hypothalamic arcuate nucleus, resulting in significant decreases in hypothalamic β-endorphin. In addition, the EV treatment causes a selective increase in µ-opioid binding in the medial preoptic area (MPOA). Since β-endorphin neurons located in the arcuate nucleus project extensively to the MPOA, we have hypothesized that the EV-induced loss of these afferents induces a compensatory upregulation of µ-opioid receptors in opioid target neurons. In order to test this hypothesis, we have utilized monosodium glutamate (MSG) treated animals as a model of β-endorphin cell loss and hence of β-endorphin deafferentation of the MPOA. Neonatal MSG treatment has been shown to result in the destruction of 80-90% of arcuate neurons accompanied by pronounced decreases in β-endorphin concentrations in both arcuate nucleus and MPOA. µ-Opioid binding sites were radioautographically labeled in sections from the MPOA of sham- and MSG-injected animals using the methionine enkephalin analogue ¹²⁵I-FK 33-824 and quantitated by computer-assisted densitometry. The remainder of the hypothalamus of these same animals was utilized for the determination of the β-endorphin concentration. The hypothalami of rats treated with MSG exhibited 62% (p < 0.01) less β-endorphin than saline-injected controls. In addition, the mean µ-opioid-binding densities in the MPOA were 24% (p < 0.05) above controls in the MSG-treated group. Linear regression analysis of hypothalamic β-endorphin concentrations and µ-opioid-binding densities within the same animals yielded an inverse proportional relationship with a coefficient of correlation of-0.85 and a goodness of fit of 0.7. These results substantiate the hypothesis that EV-induced destruction of β-endorphin neurons in the arcuate nucleus may result in chronic µ-opioid receptor upregulation in the MPOA and further suggest that β-endorphin may regulate µ-opioid receptor density in this area.

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Differential coupling of opioid binding sites to guanosine triphosphate binding regulatory proteins in subcellular fractions of rat brain

Szücs

Coscia

1992

J of Neuroscience Research

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In this study, we present evidence for the occurrence of mu, delta, and kappa opioid binding sites in synaptic plasma membranes (SPM) and microsomes of rat brain. Binding to all three opioid classes was inhibited by 5'-guanylylimidodiphosphate (Gpp[NH]p) in SPM, while microsomal sites proved to be insensitive to this GTP analog. Sensitivity was restored upon solubilization of microsomes with digitonin, suggesting that opioid receptors are physically separated from G proteins in this fraction. Modulation of microsomal binding by Na+ and Mn++ was greater than that of SPM. Pertussis toxin-catalyzed adenosine diphosphate (ADP) ribosylation revealed the presence of G proteins with alpha-subunit molecular weights of 40 kDa in both subcellular fractions. Basal low Km GTPase activity in SPM was greater than in microsomes. Etorphine elicited a concentration-dependent stimulation of guanosine triphosphatase (GTPase) activity in SPMs but not in microsomes, indicating functional coupling of opioid receptors to G protein in the former and an uncoupling in the latter. Microsomes from 3-day-old rat brain contained more mu opioid sites and they were more sensitive to Gpp(NH)p inhibition than those in adults. These results are consistent with the hypothesis that opioid binding sites in adult microsomes are internalized and G protein uncoupled, while those in neonates are newly synthesized, coupled receptors.

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Differential up-regulation of microsomal and synaptic membrane μ opioid receptors

Cited by 14 publications

References 11 publications

Chronic Morphine-Induced Changes in μ-Opioid Receptors and G Proteins of Different Subcellular Loci in Rat Brain

Chronic Morphine-Induced Changes in μ-Opioid Receptors and G Proteins of Different Subcellular Loci in Rat Brain

Monosodium Glutamate-lnduced Reductions in Hypothalamic Beta-Endorphin Content Result in Mu-Opioid Receptor Upregulation in the Medial Preoptic Area

Differential coupling of opioid binding sites to guanosine triphosphate binding regulatory proteins in subcellular fractions of rat brain

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