Dose-dependent conditioned place preference produced by etonitazene and morphine

Sala, Mariaelvina; Braida, Daniela; Calcaterra, P.; Leone, M.P.; Gori, E

doi:10.1016/0014-2999(92)90508-2

Cited by 30 publications

(6 citation statements)

References 34 publications

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“…Because only one dose of each drug was examined, it cannot be determined from the place-conditioning data alone whether these differences in sensitivity reflect potency or efficacy differences between the two groups. However, it is unlikely that the effects observed at the selected doses were atypical, as both mu-opiods (Sala et al 1992;Steinpreis et al 1996;Zarrindast et al 2004) and kappa-opiods (Shippenberg and Herz 1988;Suzuki et al 1992;Funada et al 1993) produce linear effects in this procedure.…”

Section: Discussionmentioning

confidence: 95%

Social and environmental influences on opioid sensitivity in rats: importance of an opioid’s relative efficacy at the mu-receptor

et al. 2005

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Section: Discussionmentioning

confidence: 95%

Social and environmental influences on opioid sensitivity in rats: importance of an opioid’s relative efficacy at the mu-receptor

et al. 2005

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“…In vivo , morphine does not promote significant µ receptor down‐regulation even under conditions that induce profound cellular tolerance (Stafford et al ., 2001; Gomes et al ., 2002; Patel et al ., 2002; Pawar et al ., 2007; Grecksch et al ., 2011). When administered chronically at equieffective analgesic doses, etonitazene or methadone, which are potent inducers of µ receptor internalization, produce less tolerance than morphine (Sala et al ., 1992; Elmer et al ., 1993; Gerak and France, 1996; 1997; Walker and Young, 2001; Grecksch et al ., 2006; Hull et al ., 2009). We found that GRK5 selectively contributes to morphine‐induced Ser 375 phosphorylation in mouse brain.…”

Section: Discussionmentioning

confidence: 99%

“…However, morphine is a particularly poor inducer of µ‐opioid receptor endocytosis, but a potent inducer of cellular tolerance (Arden et al ., 1995; Keith et al ., 1996; Alvarez et al ., 2001; Schulz et al ., 2004; Gintzler and Chakrabarti, 2006; Johnson et al ., 2006; McPherson et al ., 2010). Conversely, full agonists such as fentanyl or etonitazene elicit robust µ receptor internalization but less tolerance (Elmer et al ., 1993; Gerak and France, 1996; 1997; Sala et al ., 1992; Walker and Young, 2001; Grecksch et al ., 2006; 2011; Hull et al ., 2009). We have recently generated phosphosite‐specific antibodies for the carboxyl‐terminal residues threonine 370 (Thr 370 ) and serine 375 (Ser 375 ), which enabled us to selectively detect either the Thr 370 ‐phosphorylated or the Ser 375 ‐phosphorylated form of the µ receptor.…”

Section: Introductionmentioning

confidence: 99%

Deciphering µ‐opioid receptor phosphorylation and dephosphorylation in HEK293 cells

Doll

Pöll

Peuker

et al. 2012

British J Pharmacology

143

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BACKGROUND AND PURPOSEThe molecular basis of agonist-selective signalling at the m-opioid receptor is poorly understood. We have recently shown that full agonists such as [D-Ala ), and that is followed by a robust receptor internalization. In contrast, morphine promotes a selective phosphorylation of Ser 375 without causing rapid receptor internalization. EXPERIMENTAL APPROACHHere, we identify kinases and phosphatases that mediate agonist-dependent phosphorylation and dephosphorylation of the m-opioid receptor using a combination of phosphosite-specific antibodies and siRNA knock-down screening in HEK293 cells. KEY RESULTSWe found that DAMGO-driven phosphorylation of Thr 370 and Ser 375 was preferentially catalysed by G-protein-coupled receptor kinases (GRKs) 2 and 3, whereas morphine-driven Ser 375 phosphorylation was preferentially catalysed by GRK5. On the functional level, inhibition of GRK expression resulted in enhanced m-opioid receptor signalling and reduced receptor internalization. Analysis of GRK5-deficient mice revealed that GRK5 selectively contributes to morphine-induced Ser 375 phosphorylation in brain tissue. We also identified protein phosphatase 1g as a m-opioid receptor phosphatase that catalysed Thr 370 and Ser 375 dephosphorylation at or near the plasma membrane within minutes after agonist removal, which in turn facilitates receptor recycling. CONCLUSIONS AND IMPLICATIONSTogether, the morphine-activated m-opioid receptor is a good substrate for phosphorylation by GRK5 but a poor substrate for GRK2/3. GRK5 phosphorylates m-opioid receptors selectively on Ser 375 , which is not sufficient to drive significant receptor internalization.

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“…First, we attempted to bypass the problem by using an opioid with a very high potency. Etonitazene has been estimated to be 2000 times more potent than morphine in eliciting analgesia (Rosow et al 1980), and it produces dose-dependent place preference at doses as low as 2.5-15 gg/kg IP (Sala et al 1992). Therefore, pharmacologically active amounts can be obtained by drinking only moderate volumes of weak solutions with very little bitter taste.…”

Section: Discussionmentioning

confidence: 97%

Oral etonitazene and cocaine consumption by AA, ANA and Wistar rats

Hyyatiä¹,

Sinclair²

1993

Psychopharmacology

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It has been previously suggested that drug-seeking behavior maintained by alcohol, opioids, and cocaine may have some common genetic determinants. Therefore, the present study examined the intake of etonitazene, a potent opioid agonist, and cocaine by alcohol-preferring AA (Alko, Alcohol), alcohol-avoiding ANA (Alko, Non-alcohol), and Wistar rats in a two-bottle choice test. The animals, housed in single cages, were given a choice between tap water and ascending concentrations of etonitazene (0.5, 1.0, 2.0, and 4.0 micrograms/ml) or cocaine (0.2, 0.4, 0.8, and 1.6 mg/ml) solutions prepared in water. Finally, to assess the sensitivity to bitter taste by these strains, a quinine preference test with ascending quinine concentrations was conducted. The clearest line differences were found with etonitazene: at all concentrations, the AAs consumed significantly more etonitazene than the ANAs and Wistars that showed no differences. The highest etonitazene intake by the AAs, 181 micrograms/kg/day at the concentration of 4.0 micrograms/kg, produced apparent signs of opioid intoxication and withdrawal. The AAs also drank more cocaine solution than the other lines. Since, however, the pattern of cocaine intake as a function of concentration resembled that with quinine, the line differences in cocaine consumption may partly be accounted for by the differential sensitivity to bitter taste by the lines. In contrast, the marked line differences in the intake of the etonitazene solutions, which had only a slightly bitter taste, seem more likely to have been produced by the post-ingestional effects of the opioid.

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Dose-dependent conditioned place preference produced by etonitazene and morphine

Cited by 30 publications

References 34 publications

Social and environmental influences on opioid sensitivity in rats: importance of an opioid’s relative efficacy at the mu-receptor

Social and environmental influences on opioid sensitivity in rats: importance of an opioid’s relative efficacy at the mu-receptor

Deciphering µ‐opioid receptor phosphorylation and dephosphorylation in HEK293 cells

Oral etonitazene and cocaine consumption by AA, ANA and Wistar rats

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