Comparison of in vivo and in vitro parameters of opiate receptor binding in naive and tolerant/dependent rodents

Höllt, Volker; Dum, Jane; Bläsig, J; Schubert, Peter; Herz, A.

doi:10.1016/0024-3205(75)90284-2

Cited by 101 publications

(12 citation statements)

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“…However, the evidence for receptor affinity changes as the basis of tolerance is controversial. Many studies have reported no change in -receptor affinity after chronic treatment with morphine or other -agonist (Hollt et al, 1975;Rogers and el-Fakahany, 1986;Tao et al, 1987Tao et al, , 1990Besse et al, 1992;Polastron et al, 1994), whereas a few studies have reported either increased (Abdelhamid and Takemori, 1991) or decreased (Rothman et al, 1991) affinity. However, most of this work was carried out on brain tissue, rather than spinal cord.…”

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confidence: 99%

Morphine Tolerance in Spinal Cord Is Due to Interaction between μ- and δ-Receptors

Riba

Ben

Smith

et al. 2002

J Pharmacol Exp Ther

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When the opioid agonist morphine is given chronically and systemically to mice by pellet implantation for 3 days, the animals develop substantial tolerance to the antinociceptive effect of a test dose of morphine given systemically. When the test dose is administered to the spinal cord, however, very little tolerance is observed. We tested six strains of mice differing in the degree to which they develop systemic tolerance to morphine and found that none of them developed significant tolerance to spinal morphine. However, most of these strains did develop substantial spinal tolerance to antinociception induced by the selective -ag- ]-enkephalin (DPDPE). Moreover, in naïve animals, the antinociceptive effect of both DAMGO and DPDPE was blocked by D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH 2 , a selective -antagonist, indicating that both agonists mediate antinociception in the spinal cord through -receptors. In addition to directly mediating antinociception, however, DPDPE potentiated the antinociceptive activity of DAMGO in the spinal cord of naïve animals, and this antinociception was blocked by the ␦-antagonist H-TyrTicPsi[CH 2 NH]Phe-Thr-OH (TIPP), indicating mediation through ␦-receptors. In contrast, in tolerant animals, TIPP enhanced the antinociception of DAMGO. These results thus demonstrate not only that -and ␦-opioid receptors interact in naïve animals, but that the nature of this interaction changes during tolerance, from a potentiation to an inhibition. The lack of tolerance to spinal morphine may result from the ability of morphine to act as a partial antagonist at ␦-receptors.There are three major types of opioid receptors in the mammalian central nervous system, , ␦, and , encoded by distinct, although homologous genes (Satoh and Minami, 1995), and they differ in sensitivity to agonists. A preponderance of evidence indicates that opioid antinociception is mediated via the -receptor (Fang et al., 1986;Matthes et al., 1996;Sora et al., 1997), although ␦-and -receptors can also mediate this effect in at least some central nervous system locations and some antinociceptive tests Qi et al., 1990;Sofuoglu et al., 1991). However, several lines of evidence suggest that interactions among different types of opioid receptors may also contribute to the pharmacology of these drugs. This evidence is both pharmacological and biochemical. Pharmacologically, it has been shown that activation of one opioid receptor type can alter the sensitivity to agonist of a different receptor type in the same location, or of the same receptor type in a different location. Examples of the first type of interaction include potentiation of -receptor agonist-induced antinociception by ␦-receptor agonist in the brain (Heyman et al., , 1989 or spinal cord (Larson et al., 1980;He and Lee, 1998). Examples of the second type of effect include synergistic (mutually potentiating) effects of -agonists in the brain and spinal cord or between different regions in the brain (Yeung and Rudy, 1980;Roerig et al., 1984;Bodnar et al., 1991;Ros...

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confidence: 99%

Morphine Tolerance in Spinal Cord Is Due to Interaction between μ- and δ-Receptors

Riba

Ben

Smith

et al. 2002

J Pharmacol Exp Ther

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“…Previous studies have examined the molecular mechanisms underlying opiate tolerance. Chronic treatment of animals with opiates has not revealed a functionally significant change in opioid receptor number (4,5) or mRNA levels (Ref. 6, but see also Refs.…”

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μ and δ Opioid Receptors Are Differentially Desensitized by the Coexpression of β-Adrenergic Receptor Kinase 2 and β-Arrestin 2 in Xenopus Oocytes

Kovoor

Nappey

Kieffer

et al. 1997

Journal of Biological Chemistry

125

136

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The Xenopus oocyte expression system was used to test the hypothesis that homologous opioid receptor desensitization results from receptor phosphorylation by G protein-coupled receptor kinases. Activation of ␦ (DOR), (MOR) opioid, or ␤ 2 -adrenergic receptors increased K ؉ conductance in oocytes coexpressing the G protein-gated inwardly rectifying K ؉ channel subunits GIRK1 and GIRK4, and the intrinsic rate of desensitization was small. Coexpression of ␤-adrenergic receptor kinase 2 (␤-ARK2) and ␤-arrestin 2 (␤-arr2) synergistically produced a rapid desensitization of both DOR and ␤2-adrenergic receptor signaling with a t1 ⁄2 < 4 min. ␤-ARK2 and ␤-arr2 more slowly desensitized MOR responses; a similar synergistic effect on MOR required 2-3 h of agonist treatment. DOR mutants lacking serine and threonine residues at the end of the cytoplasmic tail coupled effectively to GIRK channels but were insensitive to ␤-ARK2 and ␤-arr2. However, a DOR mutant having serine residues mutated to alanine in the third cytoplasmic loop was indistinguishable in coupling and desensitization from the wild type DOR. These studies establish that opioid receptors can be regulated by ␤-ARK2 and ␤-arr2 and that a portion of the COOH terminus of DOR enhances sensitivity to this modulation.Opioid agonists are the drugs of choice in the management of severe and chronic pain; however, continuous use of opioids can cause undesirable side effects including drug tolerance and addiction. The processes underlying tolerance are complex and involve learning mechanisms, compensatory changes in neuronal circuits, and desensitization of signal transduction mechanisms (1). Three classes of opioid receptors: , ␦, and , have been defined pharmacologically, shown to couple to G proteins of the G i /G o family, and cloned (2, 3). Previous studies have examined the molecular mechanisms underlying opiate tolerance. Chronic treatment of animals with opiates has not revealed a functionally significant change in opioid receptor number (4, 5) or mRNA levels (Ref. 6, but see also Refs. 7 and 8). However, opioid receptor desensitization has been consistently implicated as one of the molecular events accompanying tolerance (9). Continuous infusion of guinea pigs or rats with morphine results in an uncoupling of opioid receptors from associated G proteins as measured biochemically (10, 11). Recordings from single rat brain neurons of the locus coeruleus show a homologous desensitization to opioid-induced increases in potassium conductance after chronic morphine treatment (12). Prolonged morphine administration reduced the ability of DAMGO, 1 a selective opioid agonist, to stimulate [ 35 S]GTP␥S binding in distinct rat brain areas (13). Chronic morphine treatment of rats also led to a homologous (e.g. receptor-specific) desensitization of either ␦ or opioid receptor activity as measured by the ability of specific agonists to inhibit adenylyl cyclase in several brain structures (14).Termination of signaling of other G protein-coupled receptors results from agonist-depe...

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“…Early studies examining the binding of opioid receptors in brain membranes from small mammals following treatment with morphine regimens that induce tolerance did not find evidence of any changes in the binding properties of opioid receptors (8,9). There are several possible reasons for the apparent discrepancy between morphine-tolerance processes in cells maintained in culture and in rat brain in vivo.…”

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Selective changes in mu opioid receptor properties induced by chronic morphine exposure.

Werling

McMahon

Cox

1989

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

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Chronic infusion of morphine to guinea pigs produced selective changes in Im agonist binding properties in cerebrocortical membrane preparations. Employing the pselective opioid agonist MePhe4, in direct binding studies and in competition of labeled antagonist binding, we found that the major changes were a decrease in the number of sites with high affnity for agonist, a small reduction in total receptor number, and a loss in the ability of guanosine 5'-[y-thio]triphosphate to regulate binding. A fraction of high-affinity p receptors appeared to retain their high affinity for agonist and their sensitivity to guanine nucleotide analogue after the induction of morphine tolerance, possibly because the morphine concentrations achieved in brain were insufficient to uncouple all p receptors from associated guanine nucleotide-binding regulatory proteins. Some membrane preparations were treated with pertussis toxin, which has been shown to functionally uncouple IL opioid receptors from their effector systems. In these preparations, a single agonist-affinity state of the receptor was observed. The apparent dissociation constant for this affinity state in pertussis toxin-treated membranes was similar to the lower-affinity state observed in preparations from morphinetolerant animals. In contrast to the changes observed at , opioid binding sites, no significant changes in agonist affinity or binding density were observed for selective 8 or K agonists, consistent with the development of selective tolerance at Ip receptors.The mechanisms by which opiate drugs induce tolerance and dependence are not clearly understood. A number of observations suggest that changes occur in the function of the receptors through which the tolerance-inducing drug acts to evoke its primary pharmacologic effect. A significant fraction of the receptors must be activated for tolerance and dependence to develop (1,2). In tissues where more than one type of opioid receptor is present, the occurrence of receptorselective tolerance (3-5) also suggests that receptor-specific mechanisms are critical in the tolerance process. Studies of the interaction of agonists with 8 opioid receptors in NG108-15 neuroblastoma-glioma hybrid cells in culture after chronic receptor activation have demonstrated that sustained agonist exposure leads initially to a loss of the ability of 8 agonists to regulate their effector system (in this case, to inhibit adenylate cyclase), followed later by a reduction in the number of 8 receptors detected by radiolabeled ligand binding (6). Recently, similar results have been reported in a study of the chronic activation by morphine of 1 opioid receptors in 7315c pituitary tumor cells maintained in primary culture (7). Thus, in these cell systems in which opioid receptors negatively regulate adenylate cyclase, sustained exposure to morphine resulted in an initial desensitization followed by receptor down-regulation.Early studies examining the binding of opioid receptors in brain membranes from small mammals following treatment wi...

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Comparison of in vivo and in vitro parameters of opiate receptor binding in naive and tolerant/dependent rodents

Cited by 101 publications

References 4 publications

Morphine Tolerance in Spinal Cord Is Due to Interaction between μ- and δ-Receptors

Morphine Tolerance in Spinal Cord Is Due to Interaction between μ- and δ-Receptors

μ and δ Opioid Receptors Are Differentially Desensitized by the Coexpression of β-Adrenergic Receptor Kinase 2 and β-Arrestin 2 in Xenopus Oocytes

Selective changes in mu opioid receptor properties induced by chronic morphine exposure.

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