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Modulation of Fas receptor proteins and dynamin during opiate addiction and induction of opiate withdrawal in rat brain

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Abstract

The Fas receptor is involved in the regulation of apoptosis but also can function as a non-apoptotic signal transducer. This study was mainly designed to quantitate Fas proteins in rat brain during heroin addiction and opiate withdrawal. In rat, mouse and human brains, and in SH-SY5Y cells, similar forms of Fas were immunodetected with different antibodies (i.e., 35 kDa native Fas and 48- and 51-kDa glycosylated Fas). Acute (2 h) treatments with the μ-opioid receptor agonists heroin (10 mg/kg) and morphine (30 mg/kg) increased the immunodensity of native Fas (124% and 36%) but not that of glycosylated Fas in the cerebral cortex. Chronic (5 days) heroin (5–30 mg/kg) and morphine (10–100 mg/kg) were also associated with increased native Fas (76% and 45%) and with different expressions of glycosylated Fas. In heroin-dependent rats, opiate withdrawal (48 h) resulted in a sustained increase in native Fas (107%) and in up-regulation of 51 kDa glycosylated Fas (51%). Acute treatments with selective δ-receptor (SNC-80, 10 mg/kg) or κ-receptor (U 50488-H, 10 mg/kg) agonists did not alter the content of native or glycosylated Fas. Chronic pentazocine (10–80 mg/kg, 5 days), a mixed opiate drug and σ1 receptor agonist, decreased native (48%) and glycosylated (38–82%) Fas proteins. Similarly, the selective σ1 agonist (+)-SKF 10047 also decreased native Fas (37%) and the effect was blocked by the σ1 antagonist BD 1063. Brain dynamin was up-regulated by acute and/or chronic heroin (30–39%), morphine (47–85%), pentazocine (51%) and heroin withdrawal (74%). The main results indicate that chronic heroin/morphine treatment and heroin withdrawal are associated with up-regulation of 35 kDa native Fas (and with different expressions of glycosylated Fas), and also with concomitant increases of dynamin in rat brain.

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References

  • Adachi M, Suematsu S, Kondo T, Ogasawara T, Tanaka T, Yoshida N, Nagata S (1995) Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver. Nat Gen 11:294–300

    CAS  PubMed  Google Scholar 

  • Badorff C, Ruetten H, Mueller S, Stahmer M, Gehring D, Jung F, Ihling C, Zeiher AM, Dimmeler S (2002) Fas receptor signaling inhibits glycogen synthase kinase 3β and induces cardiac hypertrophy following pressure overload. J Clin Invest 109:373–381

    Article  CAS  PubMed  Google Scholar 

  • Bechmann I, Mor G, Nilsen J, Eliza M, Nitsch R, Naftolin F (1999) FasL (CD95L, Apo1L) is expressed in the normal rat and human brain. Glia 27:62–74

    Google Scholar 

  • Boronat MA, García-Fuster MJ, García-Sevilla JA (2001) Chronic morphine induces up-regulation of the pro-apoptotic Fas receptor and down-regulation of the anti-apoptotic Bcl-2 oncoprotein in rat brain. Br J Pharmacol 134:1263–1270

    CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Chatzaki E, Makrigiannakis A, Margioris AN, Kouimtzoglou E, Gravanis A (2001) The Fas/FasL apoptotic pathway is involved in κ-opioid-induced apoptosis of human endometrial stromal cells. Mol Human Reprod 7:867–874

    Article  CAS  Google Scholar 

  • Choi C, Park JY, Lee J, Lim J-H, Shin E-C, Ahn Y, Kim C-H, Kim S-J, Kim J-D, Choi IS, Choi I-H (1999) Fas ligand and Fas are expressed constitutively in human astrocytes and the expression increases with IL-1, IL-6, TNF-α, or IFN-γ. J Immunol 162:1889–1895

    CAS  PubMed  Google Scholar 

  • Craft RM, McNeil DM (2003) Agonist/antagonist properties of nalbuphine, butorphanol and (−)-pentazocine in male vs. female rats. Pharmacol Biochem Behav 75:235–245

    Article  CAS  PubMed  Google Scholar 

  • Desbarats J, Birge RB, Minouni-Rongy M, Weistein DE, Palerme J-S, Newell MK (2003) Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol 5:118–125

    Article  CAS  PubMed  Google Scholar 

  • Ferrer-Alcón M, La Harpe R, Guimón J, García-Sevilla JA (2003) Down-regulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation. Neuropsychopharmacology 28:947–955

    PubMed  Google Scholar 

  • Gabilondo AM, García-Sevilla JA (1995) Spontaneous withdrawal from long-term treatment with morphine accelerates the turnover of α2-adrenoceptors in rat brain: up-regulation of receptors associated with increased receptor appearance. J Neurochem 64:2590–2597

    CAS  PubMed  Google Scholar 

  • García-Fuster MJ, Ferrer-Alcón M, Miralles A, García-Sevilla JA (2002) Modulation of pro-apoptotic Fas receptor proteins during heroin addiction in rat brain. Methods Find Exp Clin Pharmacol 24 [Suppl A]:161

  • García-Sevilla JA, Ventayol P, Busquets X, La Harpe R, Walzer C, Guimón J (1997) Marked decrease of immunolabelled 68 kDa neurofilament (NF-L) proteins in brains of opiate addicts. Neuroreport 8:1561–1565

    PubMed  Google Scholar 

  • Harlow E, Lane D (1999) Using antibodies. A laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

  • Itoh N, Yonehara S, Ishii A, Yohenara M, Mizushima S-I, Sameshima M, Hase A, Seto Y, Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233–243

    CAS  PubMed  Google Scholar 

  • Kamitani T, Nguyen HP, Yeh ETH (1997) Activation-induced aggregation and processing of the human fas antigen. Detection with cytoplasmic domain-specific antibodies. J Biol Chem 272:22307–22314

    Article  CAS  PubMed  Google Scholar 

  • Krammer PH (2000) CD95’s deadly mission in the immune system. Nature 407:789–795

    Article  CAS  PubMed  Google Scholar 

  • López E, Ferrer I (2000) Staurosporine- and H-7-induced cell death in SH-SY5Y neuroblastoma cells is associated with caspase-2 and caspase-3 activation, but not with activation of the FAS/FAS-L-caspase-8 signaling pathway. Mol Brain Res 85:61–67

    Article  PubMed  Google Scholar 

  • MacEwan DJ (2002) TNF ligands and receptors – a matter of life and death. Br J Pharmacol 135:855–875

    CAS  PubMed  Google Scholar 

  • Matsuno K, Senda T, Kobayashi T, Mita S (1995) Involvement of σ1 receptor in (+)-N-allylnormetazocine-stimulated hippocampal cholinergic functions in rats. Brain Res 690:200–206

    Article  CAS  PubMed  Google Scholar 

  • McClure SJ, Robinson PJ (1996) Dynamin, endocytosis and intracellular signalling. Mol Membr Biol 13:189–215

    CAS  PubMed  Google Scholar 

  • McCracken KA, Bowen WD, Matsumoto RR (1999) Novel σ receptor ligands attenuate the locomotor stimulatory effects of cocaine. Eur J Pharmacol 365:35–38

    Article  CAS  PubMed  Google Scholar 

  • Mei J, Pasternak W (2001) Molecular cloning and pharmacological characterization of the rat sigma1 receptor. Biochem Pharmacol 62:349–355

    Article  CAS  PubMed  Google Scholar 

  • Mei J, Pasternak W (2002) σ1 Receptor modulation of opioid analgesia in the mouse. J Pharmacol Exp Ther 300:1070–1074

    Article  CAS  PubMed  Google Scholar 

  • Murray SR, Evans CJ, Von Zastrow M (1998) Phosphorylation is not required for dynamin-dependent endocytosis of a truncated mutant opioid receptor. J Biol Chem 273:24987–24991

    Article  CAS  PubMed  Google Scholar 

  • Nagata S (1999) Fas ligand-induced apoptosis. Ann Rev Gen 33:29–55

    Article  CAS  Google Scholar 

  • Nagata S, Golstein P (1995) The Fas death receptor. Science 267:1449–1456

    CAS  PubMed  Google Scholar 

  • Negus SS, Brandt MR, Gatch MB, Mello NK (2003) Effects of heroin and its metabolites on schedule-controlled responding and thermal nociception in rhesus monkeys: sensitivity to antagonism by quadazocine, naltrindole and β-funaltrexamine. Drug Alcohol Depend 70:17–27

    Article  CAS  PubMed  Google Scholar 

  • Noble F, Szücs M, Kieffer B, Roques BP (2000) Overexpression of dynamin is induced by chronic stimulation of μ- but not δ-opioid receptors: relationship with μ-related morphine dependence. Mol Pharmacol 58:159–166

    CAS  PubMed  Google Scholar 

  • Oehm A, Behrmann I, Falk W, Pawlita M, Maier G, Klas C, Li-Weber M, Richards S, Dhein J, Trauth B, Ponstingl H, Krammer P (1992) Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor family. J Biol Chem 267:10709–10715

    CAS  PubMed  Google Scholar 

  • Orlinick JR, Vaishnaw AK, Elkon KB (1999) Structure and function of Fas/Fas ligand. Int Rev Immunol 18:293–308

    CAS  PubMed  Google Scholar 

  • Ozaita A, Escribá PV, García-Sevilla JA (1999) The alkylating agent EEDQ facilitates protease-mediated degradation of the human brain α2A-adrenoceptor as revealed by a sequence-specific antibody. Neurosci Lett 263:105–108

    Article  PubMed  Google Scholar 

  • Papakonstanti EA, Bakogeorgou E, Castanas E, Emmanouel DS, Hartig R, Stournaras C (1998) Early alterations of actin cytoskeleton in OK cells by opioids. J Cell Biochem 70:60–69

    Article  PubMed  Google Scholar 

  • Patel M, Gomes B, Patel V, Yoburn BC (2002) Antagonist-induced μ-opioid receptor up-regulation decreases G-protein receptor kinase-2 and dynamin-2 abundance in mouse spinal cord. Eur J Pharmacol 446:37–42

    Article  PubMed  Google Scholar 

  • Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothman RB, Su T-P, Tam SW, Taylor DP (1992) A proposal for the classification of sigma binding sites. Trends Pharmacol Sci 13:85–86

    CAS  PubMed  Google Scholar 

  • Raoul C, Estévez AG, Nishimune H, Cleveland DW, deLapeyrière O, Henderson CE, Haase G, Pettmann B (2002) Motoneuron death triggered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD1 mutations. Neuron 35:1067–1083

    PubMed  Google Scholar 

  • Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T (1994) Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol 45:330–334

    PubMed  Google Scholar 

  • Sastry PS, Rao KS (2000) Apoptosis and the nervous system. J Neurochem 74:1–20

    Article  CAS  PubMed  Google Scholar 

  • Schuller AGP, King MA, Zhang J, Bolan E, Pan Y-X, Morgan DJ, Chang A, Czick ME, Unterwald EM, Pasternak GW, Pintar JE (1999) Retention of heroin and morphine-6β-glucoronide analgesia in a new line of mice lacking exon 1 of MOR-1. Nat Neurosci 2:151–156

    Article  PubMed  Google Scholar 

  • Siegel RM, Ka-Ming Chang F, Chun HJ, Lenardo MJ (2000) The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol 1:469–474

    Article  CAS  PubMed  Google Scholar 

  • Singhal PC, Bhaskaran M, Patel J, Patel K, Kasinath BS, Duraisamy S, Franki N, Reddy K, Kapasi AA (2002) Role of P38 mitogen-activated protein kinase phosphorylation and Fas-Fas ligand interaction in morphine-induced macrophage apoptosis. J Immunol 168:4025–4033

    PubMed  Google Scholar 

  • Tada Y, O-Wang J, Takiguchi Y, Tatsumi K, Kuriyama T, Okada S, Tokuhisa T, Sakiyama S, Tagawa M (2002) A novel role for Fas ligand in facilitating antigen acquisition by dendritic cells. J Immunol 169:2241–2245

    CAS  PubMed  Google Scholar 

  • Ventayol P, Busquets X, García-Sevilla JA (1997) Modulation of immunoreactive protein kinase C-α and β isoforms and G proteins by acute and chronic treatments with morphine and other opiate drugs in rat brain. Naunyn-Schmiedebergs Arch Pharmacol 355:491–500

    Google Scholar 

  • Wajant H (2002) The Fas signalling pathway: more than a paradigm. Science 296:1635–1636

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Charboneau R, Barke RA, Loh HH, Roy S (2002) μ-Opioid receptor mediates chronic restraint stress-induced lymphocyte apoptosis. J Immunol 169:3630–3636

    CAS  PubMed  Google Scholar 

  • Watanabe-Fukunaga R, Brannan CI, Itoh N, Yonehara S, Copeland NG, Jenkins NA, Nagata S (1992) The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol 148:1274–1279

    PubMed  Google Scholar 

  • Whistler JL, Von Zastrow M (1999) Dissociation of functional roles of dynamin in receptor-mediated endocytosis and mitogenic signal transduction. J Biol Chem 274:24575–24578

    CAS  PubMed  Google Scholar 

  • Yin D, Mufson RA, Wang R, Shi Y (1999) Fas-mediated cell death promoted by opioids. Nature 397:218

    Article  PubMed  Google Scholar 

  • Yin D, Tuthill D, Mufson RA, Shi Y (2000) Chronic restraint stress promotes lymphocyte apoptosis by modulating CD95 expression. J Exp Med 191:1423–1428

    Article  CAS  PubMed  Google Scholar 

  • Yu VC, Richards ML, Sadée W (1986) A human neuroblastoma cell line expresses μ and δ opioid receptor sites. J Biol Chem 261:1065–1070

    CAS  PubMed  Google Scholar 

  • Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802–809

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by grant BFI2000–0306 from MCT (Madrid, Spain) and by grant 32.57066.99 from FNSRS (Bern, Switzerland). M.J.G.-F. was supported by a predoctoral fellowship from CSIC/MECD-Associated Units. J.A. García-Sevilla is a member of the Institut d’Estudis Catalans (Barcelona, Spain).

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  1. Laboratory of Neuropharmacology, Associate Unit of the Institute of Neurobiology “Ramón y Cajal” (CSIC), Department of Biology, University of the Balearic Islands, Cra. Valldemossa Km 7.5, 07122, Palma de Mallorca, Spain

    M. Julia García-Fuster, Antonio Miralles & Jesús A. García-Sevilla

  2. Clinical Research Unit, Department of Psychiatry, University of Geneva, HUG Belle-Idée, 2 Chemin du Petit-Bel-Air, 1225, Chêne-Bourg/GE, Switzerland

    Marcel Ferrer-Alcón & Jesús A. García-Sevilla

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  1. M. Julia García-Fuster
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Correspondence to Jesús A. García-Sevilla.

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García-Fuster, M.J., Ferrer-Alcón, M., Miralles, A. et al. Modulation of Fas receptor proteins and dynamin during opiate addiction and induction of opiate withdrawal in rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 368, 421–431 (2003). https://doi.org/10.1007/s00210-003-0801-9

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