Tầm quan trọng của các biến thể splice của thụ thể mu-opioid và tính linh hoạt của các hệ quả tín hiệu của chúng đối với sự tolérance thuốc giảm đau opioid

Springer Science and Business Media LLC - Tập 41 Số 5 - Trang 855-862 - 2021
Chakrabarti, Sumita1, Liu, Nai-Jiang1, Gintzler, Alan R.1
1Department Obstetrics and Gynecology, SUNY Downstate Health Sciences University, Brooklyn, USA

Tóm tắt

Việc tăng liều opioid để kiểm soát hiệu quả cơn đau thường gắn liền với đại dịch lạm dụng opioid hiện nay. Điều này tạo ra những yêu cầu xã hội cũng như y tế để hiểu rõ hơn về các cơ chế cơ bản của sự tolérance opioid nhằm phát triển các can thiệp làm giảm thiểu tình trạng này, qua đó tối đa hóa hiệu quả giảm đau của opioid. Sự tolérance giảm đau opioid sâu sắc có thể được quan sát thấy mà không có sự giảm điều hòa thụ thể mu-opioid (MOR), tích tụ G protein MOR không kết nối, và sự giảm nhạy cảm của MOR, không có sự suy yếu phosphorylation của kinase thụ thể kết nối protein G, kết dính arrestin, hoặc nội thực bào. Do đó, chúng tôi đã khám phá các hệ quả sinh hóa thay thế có thể giải thích tốt hơn cho sự tolérance giảm đau opioid. Các phát hiện của chúng tôi cho thấy tính dẻo dai đáng kể giữa các thành phần thượng nguồn và hạ nguồn của tín hiệu thụ thể opioid và sự xuất hiện của các con đường tín hiệu thay thế là những yếu tố chính góp phần vào sự tolérance giảm đau opioid. Một ví dụ về tính dẻo dai này là các phát hiện của chúng tôi cho thấy morphine mãn tính làm gia tăng các biến thể MOR MOR-1B2 và MOR-1C1 cũng như phosphorylation ở các vị trí tận cùng C của chúng không có trong MOR-1, những sự kiện có liên quan nguyên nhân với sự chuyển dịch kết nối G protein MOR từ chủ yếu ức chế Gi/Go sang kích thích Gs đối với tín hiệu adenylyl cyclase. Các đặc điểm độc đáo của những biến thể này liên quan đến sự dễ dàng thích ứng với morphine mãn tính bằng cách thay đổi tính chất của kết nối protein G cho thấy sự phong phú và tính linh hoạt của tín hiệu MOR được tạo điều kiện bởi sự phát sinh đa dạng rộng lớn của các biến thể MOR. Hơn nữa, với các mô hình biểu hiện giải phẫu khác nhau của các biến thể MOR, các điều chỉnh phụ thuộc vào biến thể splice của MOR đối với morphine mãn tính có thể cho phép làm sáng tỏ các cơ sở cơ chế của sự tolérance và phụ thuộc mà là đặc hiệu cho từng vùng CNS và từng tế bào.

Từ khóa

#thuốc giảm đau opioid #thụ thể mu-opioid #tolérance opioid #tín hiệu thụ thể #biến thể splice

Tài liệu tham khảo

citation_journal_title=NeuroReport; citation_title=Differential in vivo internalization of MOR-1 and MOR-1C by morphine; citation_author=C Abbadie, GW Pasternak; citation_volume=12; citation_issue=14; citation_publication_date=2001; citation_pages=3069-3072; citation_doi=10.1097/00001756-200110080-00017; citation_id=CR1 citation_journal_title=NeuroReport; citation_title=Immunohistochemical localization of the carboxy terminus of the novel mu opioid receptor splice variant MOR-1C within the human spinal cord; citation_author=C Abbadie, SH Gultekin, GW Pasternak; citation_volume=11; citation_issue=9; citation_publication_date=2000; citation_pages=1953-1957; citation_doi=10.1097/00001756-200006260-00029; citation_id=CR2 citation_journal_title=Neuroscience; citation_title=Comparative immunohistochemical distributions of carboxy terminus epitopes from the mu-opioid receptor splice variants MOR-1D, MOR-1 and MOR-1C in the mouse and rat CNS; citation_author=C Abbadie, Y Pan, CT Drake, GW Pasternak; citation_volume=100; citation_issue=1; citation_publication_date=2000; citation_pages=141-153; citation_doi=10.1016/S0306-4522(00)00248-7; citation_id=CR3 citation_journal_title=J Comp Neurol; citation_title=Differential distribution in rat brain of mu opioid receptor carboxy terminal splice variants MOR-1C-like and MOR-1-like immunoreactivity: evidence for region-specific processing; citation_author=C Abbadie, YX Pan, GW Pasternak; citation_volume=419; citation_issue=2; citation_publication_date=2000; citation_pages=244-256; citation_doi=10.1002/(SICI)1096-9861(20000403)419:2<244::AID-CNE8>3.0.CO;2-R; citation_id=CR4 citation_journal_title=Neuroscience; citation_title=Presynaptic localization of the carboxy-terminus epitopes of the mu opioid receptor splice variants MOR-1C and MOR-1D in the superficial laminae of the rat spinal cord; citation_author=C Abbadie, GW Pasternak, SA Aicher; citation_volume=106; citation_issue=4; citation_publication_date=2001; citation_pages=833-842; citation_doi=10.1016/S0306-4522(01)00317-7; citation_id=CR5 citation_journal_title=Pain; citation_title=Chronic pain patients are impaired on an emotional decision-making task; citation_author=AV Apkarian, Y Sosa, BR Krauss, PS Thomas, BE Fredrickson, RE Levy, RN Harden, DR Chialvo; citation_volume=108; citation_issue=1–2; citation_publication_date=2004; citation_pages=129-136; citation_doi=10.1016/j.pain.2003.12.015; citation_id=CR6 citation_journal_title=J Neurosci; citation_title=Chronic back pain is associated with decreased prefrontal and thalamic gray matter density; citation_author=AV Apkarian, Y Sosa, S Sonty, RM Levy, RN Harden, TB Parrish, DR Gitelman; citation_volume=24; citation_issue=46; citation_publication_date=2004; citation_pages=10410-10415; citation_doi=10.1523/JNEUROSCI.2541-04.2004; citation_id=CR7 citation_journal_title=Acta Anaesthesiol Scand; citation_title=Clinical experience of long-term treatment with epidural and intrathecal opioids–a nationwide survey; citation_author=S Arner, N Rawal, LL Gustafsson; citation_volume=32; citation_publication_date=1988; citation_pages=253-259; citation_doi=10.1111/j.1399-6576.1988.tb02725.x; citation_id=CR8 citation_journal_title=Elife; citation_title=Cellular tolerance at the micro-opioid receptor is phosphorylation dependent; citation_author=S Arttamangkul, DA Heinz, JR Bunzow, X Song, JT Williams; citation_volume=7; citation_publication_date=2018; citation_pages=e34989; citation_doi=10.7554/eLife.34989; citation_id=CR9 citation_journal_title=J Neurosci; citation_title=Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics; citation_author=MN Baliki, PY Geha, AV Apkarian, DR Chialvo; citation_volume=28; citation_issue=6; citation_publication_date=2008; citation_pages=1398-1403; citation_doi=10.1523/JNEUROSCI.4123-07.2008; citation_id=CR10 citation_journal_title=FEBS Lett; citation_title=Expression of two variants of the human mu opioid receptor mRNA in SK-N-SH cells and human brain; citation_author=LA Bare, E Mansson, D Yang; citation_volume=354; citation_issue=2; citation_publication_date=1994; citation_pages=213-216; citation_doi=10.1016/0014-5793(94)01129-X; citation_id=CR11 citation_journal_title=Sensors (Basel); citation_title=Overcoming the challenges of BeiDou receiver implementation; citation_author=MZ Bhuiyan, S Soderholm, S Thombre, L Ruotsalainen, H Kuusniemi; citation_volume=14; citation_issue=11; citation_publication_date=2014; citation_pages=22082-22098; citation_doi=10.3390/s141122082; citation_id=CR12 citation_journal_title=Mol Pharmacol; citation_title=Agonist binding and desensitization of the mu-opioid receptor is modulated by phosphorylation of the C-terminal tail domain; citation_author=WT Birdsong, S Arttamangkul, JR Bunzow, JT Williams; citation_volume=88; citation_issue=4; citation_publication_date=2015; citation_pages=816-824; citation_doi=10.1124/mol.114.097527; citation_id=CR13 citation_journal_title=Biochim Biophys Acta; citation_title=Receptor-effector coupling by G proteins; citation_author=L Birnbaumer, J Abramowitz, AM Brown; citation_volume=1031; citation_issue=2; citation_publication_date=1990; citation_pages=163-224; citation_doi=10.1016/0304-4157(90)90007-Y; citation_id=CR14 citation_journal_title=Synapse; citation_title=Functional analysis of MOR-1 splice variants of the mouse mu opioid receptor gene Oprm; citation_author=EA Bolan, YX Pan, GW Pasternak; citation_volume=51; citation_issue=1; citation_publication_date=2004; citation_pages=11-18; citation_doi=10.1002/syn.10277; citation_id=CR15 citation_journal_title=Brain Res; citation_title=Chronic morphine increases mu-opiate receptor binding in rat brain: a quantitative autoradiographic study; citation_author=LS Brady, M Herkenham, JB Long, RB Rothman; citation_volume=477; citation_issue=1–2; citation_publication_date=1989; citation_pages=382-386; citation_doi=10.1016/0006-8993(89)91432-7; citation_id=CR16 citation_journal_title=Anesth Analg; citation_title=Age-dependent opioid escalation in chronic pain patients; citation_author=C Buntin-Mushock, L Phillip, K Moriyama, PP Palmer; citation_volume=100; citation_issue=6; citation_publication_date=2005; citation_pages=1740-1745; citation_doi=10.1213/01.ANE.0000152191.29311.9B; citation_id=CR17 citation_journal_title=Mol Brain Res; citation_title=Phosphorylation of Gb is augmented by chronic morphine and enhances Gbg stimulation of adenylyl cyclase activity; citation_author=S Chakrabarti, AR Gintzler; citation_volume=119; citation_issue=2; citation_publication_date=2003; citation_pages=144-151; citation_doi=10.1016/j.molbrainres.2003.09.002; citation_id=CR18 citation_journal_title=Mol Pharmacol; citation_title=Phosphorylation of Gs{alpha} influences its association with the mu-opioid receptor and is modulated by chronic morphine; citation_author=S Chakrabarti, AR Gintzler; citation_volume=72; citation_publication_date=2007; citation_pages=753-760; citation_doi=10.1124/mol.107.036145; citation_id=CR19 citation_journal_title=Mol Brain Res; citation_title=Neuroblastoma neuro2A cells stably expressing a cloned μ-opioid receptor: a specific cellular model to study acute and chronic effects of morphine; citation_author=S Chakrabarti, P-Y Law, HH Loh; citation_volume=30; citation_publication_date=1995; citation_pages=269-278; citation_doi=10.1016/0169-328X(95)00014-J; citation_id=CR20 citation_journal_title=Mol Pharmacol; citation_title=Chronic morphine augments Gβγ/Gsα stimulation of adenylyl cyclase: relevance to opioid tolerance; citation_author=S Chakrabarti, M Rivera, S-Z Yan, W-J Tang, AR Gintzler; citation_volume=54; citation_publication_date=1998; citation_pages=655-662; citation_doi=10.1124/mol.54.6.949; citation_id=CR21 citation_journal_title=Mol Pharmacol; citation_title=Chronic morphine augments adenylyl cyclase phosphorylation: relevance to altered signaling during tolerance/dependence; citation_author=S Chakrabarti, L Wang, W-J Tang, AR Gintzler; citation_volume=54; citation_publication_date=1998; citation_pages=949-953; citation_doi=10.1124/mol.54.6.949; citation_id=CR22 citation_journal_title=Proc Natl Acad Sci (USA); citation_title=Chronic morphine induces the concomitant phosphorylation and altered association of multiple signaling proteins: a novel mechanism for modulating cell signaling; citation_author=S Chakrabarti, M Oppermann, AR Gintzler; citation_volume=98; citation_publication_date=2001; citation_pages=4209-4214; citation_doi=10.1073/pnas.071031798; citation_id=CR23 citation_journal_title=Mol Brain Res; citation_title=Biochemical demonstration of mu-opioid receptor association with Gsalpha: enhancement following morphine exposure; citation_author=S Chakrabarti, A Regec, AR Gintzler; citation_volume=135; citation_issue=1–2; citation_publication_date=2005; citation_pages=217-224; citation_doi=10.1016/j.molbrainres.2004.12.016; citation_id=CR24 citation_journal_title=Mol Brain Res; citation_title=Chronic morphine acts via a protein kinase Cγ-Gβ-adenylyl cyclase complex to augment phosphorylation of Gβ and Gβγ stimulatory adenylyl cyclase signaling; citation_author=S Chakrabarti, A Regec, AR Gintzler; citation_volume=138; citation_issue=1–2; citation_publication_date=2005; citation_pages=94-103; citation_doi=10.1016/j.molbrainres.2005.04.004; citation_id=CR25 citation_journal_title=J Neurochem; citation_title=Selective upregulation of functional mu-opioid receptor splice variants by chronic opioids; citation_author=S Chakrabarti, PA Madia, AR Gintzler; citation_volume=136; citation_publication_date=2016; citation_pages=1119-1130; citation_doi=10.1111/jnc.13519; citation_id=CR26 citation_journal_title=J Neurochem; citation_title=Phosphorylation of unique C-terminal sites of the mu-opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine; citation_author=S Chakrabarti, NJ Liu, AR Gintzler; citation_publication_date=2020; citation_doi=10.1111/jnc.14863; citation_id=CR27 citation_journal_title=Proc Natl Acad Sci USA; citation_title=Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus; citation_author=C Chavkin, A Goldstein; citation_volume=81; citation_issue=22; citation_publication_date=1984; citation_pages=7253-7257; citation_doi=10.1073/pnas.81.22.7253; citation_id=CR28 citation_journal_title=Pain; citation_title=The course of opioid prescribing for a new episode of disabling low back pain: opioid features and dose escalation; citation_author=M Cifuentes, B Webster, S Genevay, G Pransky; citation_volume=151; citation_issue=1; citation_publication_date=2010; citation_pages=22-29; citation_doi=10.1016/j.pain.2010.04.012; citation_id=CR29 citation_journal_title=Mol Pharmacol; citation_title=Phosphorylation of the mu-opioid receptor at tyrosine 166 (Tyr3.51) in the DRY motif reduces agonist efficacy; citation_author=CC Clayton, MR Bruchas, ML Lee, C Chavkin; citation_volume=77; citation_issue=3; citation_publication_date=2010; citation_pages=339-347; citation_doi=10.1124/mol.109.060558; citation_id=CR30 citation_journal_title=Br J Anaesth; citation_title=Opioid tolerance: the clinical perspective; citation_author=BJ Collett; citation_volume=81; citation_issue=1; citation_publication_date=1998; citation_pages=58-68; citation_doi=10.1093/bja/81.1.58; citation_id=CR31 citation_journal_title=Pain; citation_title=Is disease progression the major factor in morphine 'tolerance' in cancer pain treatment?; citation_author=E Collin, P Poulain, A Gauvain-Piquard, G Petit, E Pichard-Leandri; citation_volume=55; citation_issue=3; citation_publication_date=1993; citation_pages=319-326; citation_doi=10.1016/0304-3959(93)90007-C; citation_id=CR32 citation_journal_title=J Pain Res; citation_title=No evidence of real progress in treatment of acute pain, 1993–2012: scientometric analysis; citation_author=DJ Correll, KV Vlassakov, I Kissin; citation_volume=7; citation_publication_date=2014; citation_pages=199-210; citation_doi=10.2147/JPR.S60842; citation_id=CR33 citation_journal_title=Mol Pharmacol; citation_title=Receptor domains regulating mu opioid receptor uncoupling and internalization: relevance to opioid tolerance; citation_author=BM Cox, AT Crowder; citation_volume=65; citation_issue=3; citation_publication_date=2004; citation_pages=492-495; citation_doi=10.1124/mol.65.3.492; citation_id=CR34 citation_journal_title=Transpl Int; citation_title=Discrepancy between mRNA expression and production of IL-2 and IL-4 by cultured graft infiltrating cells propagated from endomyocardial biopsies; citation_author=CR Daane, NM Besouw, NE Emmerik, CC Baan, AH Balk, NH Jutte, B Niesters, LM Vaessen, W Weimar; citation_volume=7; citation_issue=1; citation_publication_date=1994; citation_pages=S627-628; citation_doi=10.1111/j.1432-2277.1994.tb01459.x; citation_id=CR35 citation_journal_title=Pain; citation_title=Clinical analgesic equivalence for morphine and hydromorphone with prolonged PCA; citation_author=PJ Dunbar, CR Chapman, FP Buckley, JR Gavrin; citation_volume=68; citation_issue=2–3; citation_publication_date=1996; citation_pages=265-270; citation_doi=10.1016/S0304-3959(96)03213-7; citation_id=CR36 citation_journal_title=J Biol Chem; citation_title=Phosphorylation of Ser363, Thr370, and Ser375 residues within the carboxyl tail differentially regulates mu-opioid receptor internalization; citation_author=R Kouhen, AL Burd, LJ Erickson-Herbrandson, CY Chang, PY Law, HH Loh; citation_volume=276; citation_issue=16; citation_publication_date=2001; citation_pages=12774-12780; citation_doi=10.1074/jbc.M009571200; citation_id=CR37 citation_journal_title=J Neurosci; citation_title=Analgesic tolerance to high-efficacy agonists but not to morphine is diminished in phosphorylation-deficient S375A mu-opioid receptor knock-in mice; citation_author=G Grecksch, S Just, C Pierstorff, AK Imhof, L Gluck, C Doll, A Lupp, A Becker, T Koch, R Stumm, V Hollt, S Schulz; citation_volume=31; citation_issue=39; citation_publication_date=2011; citation_pages=13890-13896; citation_doi=10.1523/JNEUROSCI.2304-11.2011; citation_id=CR38 citation_title=The analgesic connection: the Nathan B Eddy memorial lecture; citation_inbook_title=Problems of drug dependence; citation_publication_date=1985; citation_pages=4-13; citation_id=CR39; citation_author=RW Houde; citation_publisher=Rockville citation_title=Evaluation of analgesics in patients with cancer pain; citation_inbook_title=International encyclopedia of pharmacology and therapeutics; citation_publication_date=1966; citation_pages=59-98; citation_id=CR40; citation_author=RW Houde; citation_author=SL Wallenstein; citation_author=WT Beaver; citation_publisher=Pergamon Press citation_journal_title=J Neurosci; citation_title=Enhanced opioid efficacy in opioid dependence is caused by an altered signal transduction pathway; citation_author=SL Ingram, CW Vaughan, EE Bagley, M Connor, MJ Christie; citation_volume=18; citation_issue=24; citation_publication_date=1998; citation_pages=10269-10276; citation_doi=10.1523/JNEUROSCI.18-24-10269.1998; citation_id=CR41 citation_journal_title=Proc Natl Acad Sci USA; citation_title=Phorbol ester-induced stimulation and phosphorylation of adenylyl cyclase 2; citation_author=O Jacobowitz, R Iyengar; citation_volume=91; citation_issue=22; citation_publication_date=1994; citation_pages=10630-10634; citation_doi=10.1073/pnas.91.22.10630; citation_id=CR42 citation_journal_title=Clin Pharmacokinet; citation_title=Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone; citation_author=M Kinnunen, P Piirainen, H Kokki, P Lammi, M Kokki; citation_volume=58; citation_issue=6; citation_publication_date=2019; citation_pages=705-725; citation_doi=10.1007/s40262-018-00731-3; citation_id=CR43 citation_journal_title=J Biol Chem; citation_title=Carboxyl-terminal splicing of the rat mu opioid receptor modulates agonist-mediated internalization and receptor resensitization; citation_author=T Koch, S Schulz, H Schroder, R Wolf, E Raulf, V Hollt; citation_volume=273; citation_issue=22; citation_publication_date=1998; citation_pages=13652-13657; citation_doi=10.1074/jbc.273.22.13652; citation_id=CR44 citation_journal_title=J Biol Chem; citation_title=C-terminal splice variants of the mouse mu-opioid receptor differ in morphine-induced internalization and receptor resensitization; citation_author=T Koch, S Schulz, M Pfeiffer, M Klutzny, H Schroder, E Kahl, V Hollt; citation_volume=276; citation_issue=33; citation_publication_date=2001; citation_pages=31408-31414; citation_doi=10.1074/jbc.M100305200; citation_id=CR45 citation_journal_title=J Pain; citation_title=Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling; citation_author=TM Largent-Milnes, W Guo, HY Wang, LH Burns, TW Vanderah; citation_volume=9; citation_issue=8; citation_publication_date=2008; citation_pages=700-713; citation_doi=10.1016/j.jpain.2008.03.005; citation_id=CR46 citation_journal_title=Mol Pharmacol; citation_title=Dancing with different partners: protein kinase A phosphorylation of seven membrane-spanning receptors regulates their G protein-coupling specificity; citation_author=RJ Lefkowitz, KL Pierce, LM Luttrell; citation_volume=62; citation_issue=5; citation_publication_date=2002; citation_pages=971-974; citation_doi=10.1124/mol.62.5.971; citation_id=CR47 citation_journal_title=JAMA Surg; citation_title=Enhanced recovery after surgery: a review; citation_author=O Ljungqvist, M Scott, KC Fearon; citation_volume=152; citation_issue=3; citation_publication_date=2017; citation_pages=292-298; citation_doi=10.1001/jamasurg.2016.4952; citation_id=CR48 citation_journal_title=Biochem Pharmacol; citation_title=Inhibition of morphine tolerance and physical dependence development and brain serotonin synthesis by cycloheximide; citation_author=HH Loh, FH Shen, EL Way; citation_volume=18; citation_issue=10; citation_publication_date=1969; citation_pages=2711-2721; citation_doi=10.1016/0006-2952(69)90179-8; citation_id=CR49 citation_journal_title=Pharmacol Biochem Behav; citation_title=[(35)S]GTPgammaS binding and opioid tolerance and efficacy in mouse spinal cord; citation_author=PA Madia, DM Navani, BC Yoburn; citation_volume=101; citation_issue=1; citation_publication_date=2012; citation_pages=155-165; citation_doi=10.1016/j.pbb.2011.11.001; citation_id=CR50 citation_journal_title=Lancet; citation_title=Opioids in pain management; citation_author=H McQuay; citation_volume=353; citation_issue=9171; citation_publication_date=1999; citation_pages=2229-2232; citation_doi=10.1016/S0140-6736(99)03528-X; citation_id=CR51 citation_journal_title=Life Sci; citation_title=Acute opiate tolerance in man; citation_author=HJ McQuay, RE Bullingham, RA Moore; citation_volume=28; citation_issue=22; citation_publication_date=1981; citation_pages=2513-2517; citation_doi=10.1016/0024-3205(81)90593-2; citation_id=CR52 citation_journal_title=Crit Rev Oncol Hematol; citation_title=Opioid switching in cancer pain: From the beginning to nowadays; citation_author=S Mercadante, E Bruera; citation_volume=99; citation_publication_date=2016; citation_pages=241-248; citation_doi=10.1016/j.critrevonc.2015.12.011; citation_id=CR53 citation_journal_title=Sci Signal; citation_title=Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid mu-opioid receptor desensitization; citation_author=E Miess, AB Gondin, A Yousuf, R Steinborn, N Mosslein, Y Yang, M Goldner, JG Ruland, M Bunemann, C Krasel, MJ Christie, ML Halls, S Schulz, M Canals; citation_publication_date=2018; citation_doi=10.1126/scisignal.aas9609; citation_id=CR54 citation_journal_title=J Neuroendocrinol; citation_title=Adenylyl cyclase mRNA expression does not reflect the predominant Ca2+/calmodulin-stimulated activity in the hypothalamus; citation_author=N Mons, DMF Cooper; citation_volume=6; citation_publication_date=1994; citation_pages=665-671; citation_doi=10.1111/j.1365-2826.1994.tb00633.x; citation_id=CR55 citation_journal_title=Br J Pharmacol; citation_title=Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human; citation_author=MM Morgan, MJ Christie; citation_volume=164; citation_issue=4; citation_publication_date=2011; citation_pages=1322-1334; citation_doi=10.1111/j.1476-5381.2011.01335.x; citation_id=CR56 citation_journal_title=Biomed Res Int; citation_title=Ligand-specific regulation of the endogenous mu-opioid receptor by chronic treatment with mu-opioid peptide agonists; citation_author=M Muranyi, R Cinar, O Kekesi, E Birkas, G Fabian, B Bozo, A Zentai, G Toth, EG Kicsi, M Macsai, R Dochnal, G Szabo, M Szucs; citation_volume=2013; citation_publication_date=2013; citation_pages=501086; citation_doi=10.1155/2013/501086; citation_id=CR57 citation_journal_title=Neurosci Lett; citation_title=Up-regulation of mu-opioid receptor-mediated G-protein activation in protein kinase Cgamma knockout mice following repeated naloxone treatment; citation_author=M Narita, M Suzuki, H Mizoguchi, Y Yajima, S Sakurada, LF Tseng, T Suzuki; citation_volume=338; citation_issue=2; citation_publication_date=2003; citation_pages=103-106; citation_doi=10.1016/S0304-3940(02)01354-X; citation_id=CR58 citation_journal_title=Pain Med; citation_title=Comorbidities in chronic neuropathic pain; citation_author=B Nicholson, S Verma; citation_volume=5; citation_issue=1; citation_publication_date=2004; citation_pages=S9-S27; citation_doi=10.1111/j.1526-4637.2004.04019.x; citation_id=CR59 citation_journal_title=Neuroscience; citation_title=The expression and distribution of tau proteins and messenger RNA in rat dorsal root ganglion neurons during development and regeneration; citation_author=F Nothias, L Boyne, M Murray, A Tessler, I Fischer; citation_volume=66; citation_issue=3; citation_publication_date=1995; citation_pages=707-719; citation_doi=10.1016/0306-4522(94)00598-y; citation_id=CR60 citation_journal_title=DNA Cell Biol; citation_title=Diversity and complexity of the mu opioid receptor gene: alternative pre-mRNA splicing and promoters; citation_author=YX Pan; citation_volume=24; citation_issue=11; citation_publication_date=2005; citation_pages=736-750; citation_doi=10.1089/dna.2005.24.736; citation_id=CR61 citation_journal_title=Mol Pharmacol; citation_title=Identification and characterization of three new alternatively spliced mu-opioid receptor isoforms; citation_author=YX Pan, J Xu, E Bolan, C Abbadie, A Chang, A Zuckerman, G Rossi, GW Pasternak; citation_volume=56; citation_issue=2; citation_publication_date=1999; citation_pages=396-403; citation_doi=10.1124/mol.56.2.396; citation_id=CR62 citation_journal_title=Proc Natl Acad Sci USA; citation_title=Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene; citation_author=YX Pan, J Xu, L Mahurter, E Bolan, M Xu, GW Pasternak; citation_volume=98; citation_issue=24; citation_publication_date=2001; citation_pages=14084-14089; citation_doi=10.1073/pnas.241296098; citation_id=CR63 citation_journal_title=Oprm Neuroscience; citation_title=Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene; citation_author=L Pan, J Xu, R Yu, MM Xu, YX Pan, GW Pasternak; citation_volume=133; citation_issue=1; citation_publication_date=2005; citation_pages=209-220; citation_doi=10.1016/j.neuroscience.2004.12.033; citation_id=CR64 citation_journal_title=Mol Pharmacol; citation_title=Identification of four novel exon 5 splice variants of the mouse mu-opioid receptor gene: functional consequences of C-terminal splicing; citation_author=YX Pan, J Xu, E Bolan, HS Moskowitz, M Xu, GW Pasternak; citation_volume=68; citation_issue=3; citation_publication_date=2005; citation_pages=866-875; citation_doi=10.1124/mol.105.011858; citation_id=CR65 citation_journal_title=Proc Natl Acad Sci U S A; citation_title=Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions; citation_author=YX Pan, J Xu, M Xu, GC Rossi, JE Matulonis, GW Pasternak; citation_volume=106; citation_issue=12; citation_publication_date=2009; citation_pages=4917-4922; citation_doi=10.1073/pnas.0811586106; citation_id=CR66 citation_journal_title=Trends Pharmacol Sci; citation_title=Incomplete cross tolerance and multiple mu opioid peptide receptors; citation_author=GW Pasternak; citation_volume=22; citation_issue=2; citation_publication_date=2001; citation_pages=67-70; citation_doi=10.1016/S0165-6147(00)01616-3; citation_id=CR67 citation_journal_title=Pharmacol Rev; citation_title=Mu opioids and their receptors: evolution of a concept; citation_author=W Pasternak, Y-X Pan; citation_volume=65; citation_publication_date=2013; citation_pages=1257-1317; citation_doi=10.1124/pr.112.007138; citation_id=CR68 citation_journal_title=J Neurochem; citation_title=Identification of three new alternatively spliced variants of the rat mu opioid receptor gene: dissociation of affinity and efficacy; citation_author=DA Pasternak, L Pan, J Xu, R Yu, MM Xu, GW Pasternak, YX Pan; citation_volume=91; citation_issue=4; citation_publication_date=2004; citation_pages=881-890; citation_doi=10.1111/j.1471-4159.2004.02767.x; citation_id=CR69 citation_journal_title=Mol Pharmacol; citation_title=Opioid agonists differentially regulate mu-opioid receptors and trafficking proteins in vivo; citation_author=MB Patel, CN Patel, V Rajashekara, BC Yoburn; citation_volume=62; citation_issue=6; citation_publication_date=2002; citation_pages=1464-1470; citation_doi=10.1124/mol.62.6.1464; citation_id=CR70 citation_journal_title=Pain; citation_title=Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review; citation_author=SE Rapp, LB Ready, ML Nessly; citation_volume=61; citation_issue=2; citation_publication_date=1995; citation_pages=195-201; citation_doi=10.1016/0304-3959(94)00168-E; citation_id=CR71 citation_journal_title=Eur J Immunol; citation_title=Dissociation between cytokine mRNA expression and protein production in shigellosis; citation_author=R Raqib, A Ljungdahl, AA Lindberg, B Wretlind, U Andersson, J Andersson; citation_volume=26; citation_issue=5; citation_publication_date=1996; citation_pages=1130-1138; citation_doi=10.1002/eji.1830260526; citation_id=CR72 citation_journal_title=Mol Brain Res; citation_title=Differential effect of chronic morphine on mRNA encoding adenylyl cyclase isoforms: relevance to physiological sequela of tolerance/dependence; citation_author=M Rivera, AR Gintzler; citation_volume=54; citation_publication_date=1998; citation_pages=165-169; citation_doi=10.1016/S0169-328X(97)00303-3; citation_id=CR73 citation_journal_title=J Neurosci; citation_title=Brain gray matter decrease in chronic pain is the consequence and not the cause of pain; citation_author=R Rodriguez-Raecke, A Niemeier, K Ihle, W Ruether, A May; citation_volume=29; citation_issue=44; citation_publication_date=2009; citation_pages=13746-13750; citation_doi=10.1523/JNEUROSCI.3687-09.2009; citation_id=CR74 citation_journal_title=EMBO J; citation_title=Differential regulation of HLA-DR mRNAs and cell surface antigens by interferon; citation_author=F Rosa, D Hatat, A Abadie, D Wallach, M Revel, M Fellous; citation_volume=2; citation_issue=9; citation_publication_date=1983; citation_pages=1585-1589; citation_doi=10.1002/j.1460-2075.1983.tb01628.x; citation_id=CR75 citation_journal_title=NIDA Res Monogr; citation_title=Upregulation of rat brain opioid receptors by the chronic administration of morphine: possible evidence for an anti-opiate model of tolerance and dependence; citation_author=RB Rothman, HYT Yang, JB Long; citation_volume=105; citation_publication_date=1991; citation_pages=264-270; citation_id=CR76 citation_journal_title=Ann Rheum Dis; citation_title=Discrepancy between mRNA and protein expression of tumour suppressor maspin in synovial tissue may contribute to synovial hyperplasia in rheumatoid arthritis; citation_author=J Schedel, O Distler, M Woenckhaus, RE Gay, B Simmen, BA Michel, U Muller-Ladner, S Gay; citation_volume=63; citation_issue=10; citation_publication_date=2004; citation_pages=1205-1211; citation_doi=10.1136/ard.2003.006312; citation_id=CR77 citation_journal_title=Nat Neurosci; citation_title=Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1; citation_author=AG Schuller, MA King, J Zhang, E Bolan, YX Pan, DJ Morgan, A Chang, ME Czick, EM Unterwald, GW Pasternak, JE Pintar; citation_volume=2; citation_issue=2; citation_publication_date=1999; citation_pages=151-156; citation_doi=10.1038/5706; citation_id=CR78 citation_journal_title=Science; citation_title=Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens; citation_author=N Schwartz, P Temkin, S Jurado, BK Lim, BD Heifets, JS Polepalli, RC Malenka; citation_volume=345; citation_issue=6196; citation_publication_date=2014; citation_pages=535-542; citation_doi=10.1126/science.1253994; citation_id=CR79 citation_journal_title=Synapse; citation_title=Role of cAMP-dependent protein kinase (PKA) in opioid agonist-induced mu-opioid receptor downregulation and tolerance in mice; citation_author=J Shen, A Benedict Gomes, A Gallagher, K Stafford, BC Yoburn; citation_volume=38; citation_issue=3; citation_publication_date=2000; citation_pages=322-327; citation_doi=10.1002/1098-2396(20001201)38:3<322::AID-SYN11>3.0.CO;2-1; citation_id=CR80 citation_journal_title=J Neurosci; citation_title=Effects of chronic morphine administration on mu opioid receptor-stimulated [35S]GTPgammaS autoradiography in rat brain; citation_author=LJ Sim, DE Selley, SI Dworkin, SR Childers; citation_volume=16; citation_issue=8; citation_publication_date=1996; citation_pages=2684-2692; citation_doi=10.1523/JNEUROSCI.16-08-02684.1996; citation_id=CR81 citation_journal_title=J Neurosci; citation_title=Chronic heroin self-administration desensitizes mu opioid receptor-activated G-proteins in specific regions of rat brain; citation_author=LJ Sim-Selley, DE Selley, LJ Vogt, SR Childers, TJ Martin; citation_volume=20; citation_issue=12; citation_publication_date=2000; citation_pages=4555-4562; citation_doi=10.1523/JNEUROSCI.20-12-04555.2000; citation_id=CR82 citation_journal_title=Anesthesiology; citation_title=Differential cross-tolerance between intrathecal morphine and sufentanil in the rat; citation_author=M Sosnowski, TL Yaksh; citation_volume=73; citation_issue=6; citation_publication_date=1990; citation_pages=1141-1147; citation_doi=10.1097/00000542-199012000-00012; citation_id=CR83 citation_journal_title=Anesthesiology; citation_title=Studies of morphine and D-ala2-D-leu5-enkephalin (DADLE) cross-tolerance after continuous intrathecal infusion in the rat; citation_author=CW Stevens, TL Yaksh; citation_volume=76; citation_issue=4; citation_publication_date=1992; citation_pages=596-603; citation_doi=10.1097/00000542-199204000-00017; citation_id=CR84 citation_journal_title=Neuroscience; citation_title=[d-Ala2, N-MePhe4, Gly-ol5]enkephalin-induced internalization of the micro opioid receptor in the spinal cord of morphine tolerant rats; citation_author=JA Trafton, AI Basbaum; citation_volume=125; citation_issue=3; citation_publication_date=2004; citation_pages=541-543; citation_doi=10.1016/j.neuroscience.2004.02.019; citation_id=CR85 citation_journal_title=J Neurosci; citation_title=Gi-mediated stimulation of type II adenylyl cyclase is augmented by Gq-coupled receptor activation and phorbol ester treatment; citation_author=RC Tsu, YH Wong; citation_volume=16; citation_issue=4; citation_publication_date=1996; citation_pages=1317-1323; citation_doi=10.1523/JNEUROSCI.16-04-01317.1996; citation_id=CR86 citation_journal_title=J Neurochem; citation_title=Mu-opioid receptor splice variants: sex-dependent regulation by chronic morphine; citation_author=V Verzillo, PA Madia, N-J Liu, AR Gintzler; citation_volume=130; citation_publication_date=2014; citation_pages=790-796; citation_doi=10.1111/jnc.12768; citation_id=CR87 citation_journal_title=Pharmacology; citation_title=Pharmacodynamics and kinetics of loss of tolerance and physical dependence on morphine induced by pellet implantation in the rat; citation_author=VM Villar, HN Bhargava; citation_volume=45; citation_issue=6; citation_publication_date=1992; citation_pages=319-328; citation_doi=10.1159/000139017; citation_id=CR88 citation_journal_title=Br J Pharmacol; citation_title=Contribution of adrenomedullin to the switch of G protein-coupled mu-opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats; citation_author=D Wang, J Zeng, Q Li, J Huang, R Couture, Y Hong; citation_volume=173; citation_issue=7; citation_publication_date=2016; citation_pages=1196-1207; citation_doi=10.1111/bph.13419; citation_id=CR89 citation_journal_title=J Biol Chem; citation_title=Molecular cloning and characterization of the type VII isoform of mammalian adenylyl cyclase expressed widely in mouse tissues and in S49 mouse lymphoma cells; citation_author=PA Watson, J Krupinski, AM Kempinski, CD Frankenfield; citation_volume=269; citation_issue=46; citation_publication_date=1994; citation_pages=28893-28898; citation_doi=10.1016/S0021-9258(19)61991-5; citation_id=CR90 citation_journal_title=Science; citation_title=Morphine tolerance, physical dependence, and synthesis of brain 5-hydroxytryptamine; citation_author=EL Way, HH Loh, F Shen; citation_volume=162; citation_issue=3859; citation_publication_date=1968; citation_pages=1290-1292; citation_doi=10.1126/science.162.3859.1290; citation_id=CR91 citation_journal_title=Pharmacol Rev; citation_title=Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance; citation_author=JT Williams, SL Ingram, G Henderson, C Chavkin, M Zastrow, S Schulz, T Koch, CJ Evans, MJ Christie; citation_volume=65; citation_issue=1; citation_publication_date=2013; citation_pages=223-254; citation_doi=10.1124/pr.112.005942; citation_id=CR92 citation_journal_title=Proc Natl Acad Sci USA; citation_title=Stabilization of morphine tolerance with long-term dosing: association with selective upregulation of mu-opioid receptor splice variant mRNAs; citation_author=J Xu, AJ Faskowitz, GC Rossi, M Xu, Z Lu, YX Pan, GW Pasternak; citation_volume=112; citation_issue=1; citation_publication_date=2015; citation_pages=279-284; citation_doi=10.1073/pnas.1419183112; citation_id=CR93 citation_title=Tolerance: factors involved in changes in the dose-effect relationship with chronic drug exposure; citation_inbook_title=Towards a new pharmacotherapy of pain; citation_publication_date=1991; citation_id=CR94; citation_author=TL Yaksh; citation_publisher=Wiley citation_journal_title=J Pharmacol Exp Ther; citation_title=Opioid receptor regulation in mice; citation_author=BC Yoburn, B Billings, A Duttaroy; citation_volume=265; citation_issue=1; citation_publication_date=1993; citation_pages=314-320; citation_id=CR95 citation_journal_title=J Biol Chem; citation_title=Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system; citation_author=AM Zamah, M Delahunty, LM Luttrell, RJ Lefkowitz; citation_volume=277; citation_issue=34; citation_publication_date=2002; citation_pages=31249-31256; citation_doi=10.1074/jbc.M202753200; citation_id=CR96 citation_journal_title=Proc Natl Acad Sci USA; citation_title=Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness; citation_author=JF Zhang, SS Fergusson, LS Barak, SR Bodduluri, SA Paporte, PY Law, MG Caron; citation_volume=95; citation_publication_date=1998; citation_pages=7157-7162; citation_doi=10.1073/pnas.95.12.7157; citation_id=CR97 citation_journal_title=J Biol Chem; citation_title=Protein kinase C alters the responsiveness of adenylyl cyclases to G protein alpha and betagamma subunits; citation_author=G Zimmermann, R Taussig; citation_volume=271; citation_issue=43; citation_publication_date=1996; citation_pages=27161-27166; citation_doi=10.1074/jbc.271.43.27161; citation_id=CR98 citation_journal_title=FEBS Lett; citation_title=Cloning and expression of an isoform of the rat mu opioid receptor (rMOR1B) which differs in agonist induced desensitization from rMOR1; citation_author=A Zimprich, T Simon, V Hollt; citation_volume=359; citation_issue=2–3; citation_publication_date=1995; citation_pages=142-146; citation_doi=10.1016/0014-5793(95)00028-8; citation_id=CR99