LitCovid-sentences  

PMC:7463108 / 29721-53331 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T420 0-72 Sentence denotes Cellular and Molecular Interactions in Astroglia, Microglia, and Neurons
T421 73-189 Sentence denotes Prior reviews have outlined how opiate drugs likely exacerbate neuroHIV pathology in neurons and glia (Hauser et al.
T422 190-229 Sentence denotes 2005; Dutta and Roy 2012; Hauser et al.
T423 230-248 Sentence denotes 2012; Reddy et al.
T424 249-288 Sentence denotes 2012; Hauser and Knapp 2014; Liu et al.
T425 289-309 Sentence denotes 2016a; Murphy et al.
T426 310-383 Sentence denotes 2019) including in the enteric nervous system (Galligan 2015; Meng et al.
T427 384-390 Sentence denotes 2015).
T428 391-680 Sentence denotes Opioid-HIV pathophysiological interactions are complex and differ depending on the timing and duration of co-exposure, the pharmacology of the opioid drug involved, the cell types and brain regions targeted, host and viral genetics, and are highly contextual (Hauser and Knapp 2014, 2018).
T429 681-798 Sentence denotes A summary of the cellular and molecular interactions in various CNS cell types is also reviewed in detail in Table 2.
T430 799-853 Sentence denotes Table 2 Cellular and molecular interactions (in vitro)
T431 854-937 Sentence denotes Major effects HIV pathogena ARV Opioids Outcome Model system (in vitro) Citation(s)
T432 938-948 Sentence denotes Mixed-Glia
T433 949-982 Sentence denotes HIV expression HIV No • Dynorphin
T434 983-992 Sentence denotes • U50,488
T435 993-1029 Sentence denotes (KOR agonists) • ↑ HIV-1 expression,
T436 1030-1160 Sentence denotes • Dynorphin (KOR agonist) ↑ TNF-α, IL-6 mRNA and protein Human fetal neural cells, HIV-infected promonocyte (U1) line (Chao et al.
T437 1161-1166 Sentence denotes 1995)
T438 1167-1188 Sentence denotes HIVSF162 No • U50,488
T439 1189-1198 Sentence denotes • U69,593
T440 1199-1215 Sentence denotes • Dynorphin1–17;
T441 1216-1230 Sentence denotes (KOR agonists)
T442 1231-1340 Sentence denotes • Morphine • KOR agonists ± TNF-α differentially ↓ HIV p24 Human, primary mixed neurons and glia (Chao et al.
T443 1341-1347 Sentence denotes 1998a)
T444 1348-1393 Sentence denotes Chemokines Tat1–86 No Morphine • ↑ CCL5, CCL2
T445 1394-1425 Sentence denotes • ↑ [Ca2+]i (Beclin1 dependent)
T446 1426-1482 Sentence denotes • ↓ Autophagy Mouse, primary mixed glia (Lapierre et al.
T447 1483-1488 Sentence denotes 2018)
T448 1489-1551 Sentence denotes HIVSF162 (R5) No Morphine • ↑ HIV-1 Tat-induced LTR expression
T449 1552-1616 Sentence denotes • ↑ CCR5 expression (inhibited by bivalent ligand in astrocytes)
T450 1617-1625 Sentence denotes • ↑ IL-6
T451 1626-1676 Sentence denotes • ↑ CCL5 Human, primary mixed glia (El-Hage et al.
T452 1677-1682 Sentence denotes 2013)
T453 1683-1867 Sentence denotes Glial restricted precursors: survival & MOR, DOR, KOR expression Tat1–72 No Morphine (acting via DOR and/or KOR) • ↑ Caspase-3 activation & ↑ cell death by Tat or morphine via DOR, KOR
T454 1868-1941 Sentence denotes • No opioid-Tat interactions Mouse, primary glial precursors (Buch et al.
T455 1942-1947 Sentence denotes 2007)
T456 1948-1971 Sentence denotes MOR expression in NPCs;
T457 1972-2062 Sentence denotes NPC survival and developmental fate Tat1–72 No Morphine • MOR expressed by subsets of NPCs
T458 2063-2145 Sentence denotes • ↑ Astrocyte and immature glial death Mouse, primary mixed glia (Khurdayan et al.
T459 2146-2151 Sentence denotes 2004)
T460 2152-2334 Sentence denotes MOR and CCR5 interactions Tat1–86 (from HIVIIIB) No Morphine • ↓ Neuronal survival via CCR5 activation in glia (rescued by BDNF treatment) Mouse, primary neurons and glia (Kim et al.
T461 2335-2340 Sentence denotes 2018)
T462 2341-2404 Sentence denotes HIV infectivity MOR-CCR5 dimerization HIVSF162 (R5) No Morphine
T463 2405-2527 Sentence denotes CCR5-MOR bivalent ligand 1b • MOR-CCR5 bivalent ligand blocks HIV infection in astroglia, but not microglia, with morphine
T464 2528-2688 Sentence denotes • MOR-CCR5 bivalent ligand blocks the fusion of HIV gp160 and CCR5-CD4-expressing HEK cells Human, primary astrocytes and microglia; HEK-293T cells (Yuan et al.
T465 2689-2708 Sentence denotes 2013; Arnatt et al.
T466 2709-2714 Sentence denotes 2016)
T467 2715-2862 Sentence denotes HIV expression and maturational fate of neurons and astroglia HIVBaL (R5) No Morphine • ↑ HIV p24 and ↑ Tat mRNA levels with morphine after 21 days
T468 2863-2990 Sentence denotes • ↓ Proliferation of neural progenitors; ↑ astroglial and ↑ neuronal differentiation Human, neural progenitors (Balinang et al.
T469 2991-2996 Sentence denotes 2017)
T470 2997-3007 Sentence denotes Astrocytes
T471 3008-3060 Sentence denotes HIV expression HIVSF162 (R5) No Morphine • ↑ HIV p24
T472 3061-3113 Sentence denotes • ↑ CCL2 Human, primary astrocytes (Rodriguez et al.
T473 3114-3119 Sentence denotes 2017)
T474 3120-3174 Sentence denotes Toll-like receptor (TLR) expression/function • Tat1–72
T475 3175-3235 Sentence denotes • gp120 No Morphine • ↑ TLR2 with Tat, Tat + morphine, gp120
T476 3236-3312 Sentence denotes • ↓ TLR9 with Tat, morphine, gp120 Mouse, primary astrocytes (El-Hage et al.
T477 3313-3319 Sentence denotes 2011a)
T478 3320-3365 Sentence denotes Chemokines Tat1–72 No Morphine • ↑ CCL5, CCL2
T479 3366-3374 Sentence denotes • ↑ IL-6
T480 3375-3428 Sentence denotes • ↑ [Ca2+]i Mouse, primary astrocytes (El-Hage et al.
T481 3429-3434 Sentence denotes 2005)
T482 3435-3463 Sentence denotes Tat1–72 No Morphine • ↑ CCL2
T483 3464-3472 Sentence denotes • ↑ CCL5
T484 3473-3539 Sentence denotes • ↑ Microglial migration Mouse, primary astrocytes (El-Hage et al.
T485 3540-3546 Sentence denotes 2006a)
T486 3547-3592 Sentence denotes Tat1–72 No Morphine • ↑ CCL2, ↑ IL-6, ↑ TNF-α
T487 3593-3604 Sentence denotes • ↑ [Ca2+]i
T488 3605-3644 Sentence denotes • ↑ NF-κB trafficking and transcription
T489 3645-3732 Sentence denotes • No interaction / acceleration with morphine Mouse, primary astrocytes (El-Hage et al.
T490 3733-3739 Sentence denotes 2008b)
T491 3740-3770 Sentence denotes Tat No • U50,488 (KOR agonist)
T492 3771-3814 Sentence denotes • Nor-BNI (KOR antagonist) • U50,488 ↓ CCL2
T493 3815-3872 Sentence denotes • U50,488 ↓ NF-κB Human, primary astrocytes (Sheng et al.
T494 3873-3878 Sentence denotes 2003)
T495 3879-3916 Sentence denotes N/A No Morphine • ↑ CCR5, CCR3, CXCR2
T496 3917-4000 Sentence denotes • ↓ IL-8, CCL4 Human, astrocytoma U87 cell line, primary astrocytes (Mahajan et al.
T497 4001-4006 Sentence denotes 2002)
T498 4007-4016 Sentence denotes • Tat1–86
T499 4017-4160 Sentence denotes • gp120IIIB No Morphine Regional differences in cytokine and ROS production —differed for each insult Mouse, primary astrocytes (Fitting et al.
T500 4161-4167 Sentence denotes 2010a)
T501 4168-4212 Sentence denotes Oxidative stress / damage Tat1–72 No • DPDPE
T502 4213-4221 Sentence denotes • SNC-80
T503 4222-4336 Sentence denotes (DOR agonists) DOR agonists ↓ Tat-induced oxidative stress Human derived brain cell line (SK-N-SH) (Wallace et al.
T504 4337-4342 Sentence denotes 2006)
T505 4343-4387 Sentence denotes Inflammation, maturation /plasticity • Tat86
T506 4388-4549 Sentence denotes • Tat101 No Morphine ↓ β-catenin signaling and variably decreases TrkB, BDNF, and NLRP1 mRNA in fetal astrocytes b Human, U87MG and fetal astrocytes (Chen et al.
T507 4550-4555 Sentence denotes 2020)
T508 4556-4565 Sentence denotes Microglia
T509 4566-4614 Sentence denotes HIV replication HIVSF162 (R5) No • Endomorphin-1
T510 4615-4630 Sentence denotes • Endomorphin-2
T511 4631-4699 Sentence denotes (MOR agonists) • ↑ HIV p24 with endomorphin-1, but not endomorphin-2
T512 4700-4789 Sentence denotes • Endomorphin-1 acts via MOR, but not DOR / KOR Human, primary microglia (Peterson et al.
T513 4790-4795 Sentence denotes 1999)
T514 4796-4872 Sentence denotes HIVSF162 (R5) No Morphine ↑ HIV p24 Human, primary microglia (El-Hage et al.
T515 4873-4878 Sentence denotes 2014)
T516 4879-4929 Sentence denotes HIVSF162 (R5) No • U50,488; U69,593 (KOR agonists)
T517 4930-4995 Sentence denotes • Dynorphin Al-13 ↓ HIV p24 Human, primary microglia (Chao et al.
T518 4996-5002 Sentence denotes 1996b)
T519 5003-5018 Sentence denotes • HIVJR-FL (R5)
T520 5019-5060 Sentence denotes • gp120 No β-endorphin • ↑ HIV expression
T521 5061-5096 Sentence denotes • ↑ HIV p24 (14-day post infection)
T522 5097-5160 Sentence denotes • gp120 ↑ IL-1, TNF, IL-6 Human, fetal microglia (Sundar et al.
T523 5161-5166 Sentence denotes 1995)
T524 5167-5210 Sentence denotes HIVSF162 No • 8-CAC, U50,488 (KOR agonists)
T525 5211-5268 Sentence denotes • Cocaine • KOR agonist ↓ p24; blocked by KOR antagonists
T526 5269-5356 Sentence denotes • KOR agonist negates cocaine-induced ↑ HIV Human, fetal brain microglia (Gekker et al.
T527 5357-5362 Sentence denotes 2004)
T528 5363-5390 Sentence denotes HIVSF162 No OPRL1 antisense
T529 5391-5467 Sentence denotes Nociceptin / orphanin FQ (OPRL1 agonist) • OPRL1 antisense (and sense) ↓ p24
T530 5468-5563 Sentence denotes • Nociceptin, no effect on p24 Human, fetal brain microglia and mixed neurons/glia (Chao et al.
T531 5564-5570 Sentence denotes 1998b)
T532 5571-5596 Sentence denotes HIV expression • HIVSF162
T533 5597-5659 Sentence denotes • Tat ZDV U50,488 (KOR agonist) • ↓ p24 on day 14 with U50,488
T534 5660-5687 Sentence denotes • ↓ Neurotoxicity (U50,488)
T535 5688-5769 Sentence denotes • ↓ Quinolinate by microglia Human, fetal microglia and neural cells (Chao et al.
T536 5770-5775 Sentence denotes 2000)
T537 5776-5829 Sentence denotes Chemokines and Cytokines Tat1–72 No Morphine • ↑ CCR5
T538 5830-5847 Sentence denotes • ↑ CD11b, ↑ CD40
T539 5848-5874 Sentence denotes • ↑ TNF-α, ↑ IL-6, ↑ IP-10
T540 5875-5933 Sentence denotes • ↑ iNOS Mouse, BV-2 and primary microglia (Bokhari et al.
T541 5934-5939 Sentence denotes 2009)
T542 5940-5997 Sentence denotes MOR signaling Tat1–72 No Morphine • ↑ MOR (intracellular)
T543 5998-6066 Sentence denotes • ↑ MOR mRNA Mouse, N9 and primary microglia (Turchan-Cholewo et al.
T544 6067-6072 Sentence denotes 2008)
T545 6073-6149 Sentence denotes Oxidative Stress Tat1–72 No Morphine • ↑ ROS [O2− (DHE), ↑ HO2•, H2O2 (DCF)]
T546 6150-6227 Sentence denotes • ↑ Protein carbonyls Mouse, N9 and primary microglia (Turchan-Cholewo et al.
T547 6228-6233 Sentence denotes 2009)
T548 6234-6389 Sentence denotes Glutamate release Tat1–72 No Morphine ↑ Glutamate release via ↑ xc− cystine-glutamate antiporter expression/function Mouse, primary microglia (Gupta et al.
T549 6390-6395 Sentence denotes 2010)
T550 6396-6403 Sentence denotes Neurons
T551 6404-6510 Sentence denotes HIV expression HIV No Morphine ↑ HIV expression Human derived, SH-SY5Y neuroblastoma cells (Squinto et al.
T552 6511-6516 Sentence denotes 1990)
T553 6517-6572 Sentence denotes Homeostasis and Injury Tat1–86 No Morphine • ↑ [Ca2+]i,
T554 6573-6583 Sentence denotes • ↑ [Na+]i
T555 6584-6619 Sentence denotes • ↓ ΔΨm (mitochondrial) instability
T556 6620-6685 Sentence denotes • ↑ Dendritic degeneration Mouse, primary neurons (Fitting et al.
T557 6686-6692 Sentence denotes 2014a)
T558 6693-6758 Sentence denotes Mitochondrial inner membrane potential and ROS • Tat1–86, Tat1–72
T559 6759-7033 Sentence denotes • gp120 No Morphine ↑ ΔΨm instability and oxidative stress ↑ with Tat + morphine, ↑ neuroprotection with allopregnanolone Human, primary neurons ; mouse, striatal medium spiny neurons; mouse, striatal medium spiny neurons, SH-SY5Y neuroblastoma cells (Turchan-Cholewo et al.
T560 7034-7052 Sentence denotes 2006; Paris et al.
T561 7053-7058 Sentence denotes 2020)
T562 7059-7174 Sentence denotes Neuronal survival Tat1–86 No Morphine • ↓ Neuronal survival from Tat + morphine and ↓ glial CX3CL1 rescued by CX3CL
T563 7175-7280 Sentence denotes • CX3CL1 (fractalkine) regulates microglial motility Mouse, primary neurons and mixed glia (Suzuki et al.
T564 7281-7286 Sentence denotes 2011)
T565 7287-7324 Sentence denotes Tat1–86 No Morphine • ↓ Proliferation
T566 7325-7346 Sentence denotes • ↑ ERK1/2 activation
T567 7347-7362 Sentence denotes • ↑ p53 and p21
T568 7363-7432 Sentence denotes • ↓ Cyclin D1 and Akt levels Human, neuronal precursors (Malik et al.
T569 7433-7438 Sentence denotes 2014)
T570 7439-7489 Sentence denotes Tat1–72, Tat1–86 No Morphine • ↓ Neuronal survival
T571 7490-7649 Sentence denotes • ↑ Neuronal survival with ibudilast (AV411) (inhibiting glial NF-κB blocks Tat ± morphine neurotoxicity) Mouse, primary neurons and mixed glia (Gurwell et al.
T572 7650-7670 Sentence denotes 2001; El-Hage et al.
T573 7671-7676 Sentence denotes 2014)
T574 7677-7716 Sentence denotes White matter/oligodendroglial pathology
T575 7717-7842 Sentence denotes Changes in OL survival and morphology Tat1–86 No Morphine (25 mg pellet, 7 days); morphine (in vitro) • ↑ Degeneration of OLs
T576 7843-7863 Sentence denotes • ↑ TUNEL reactivity
T577 7864-7930 Sentence denotes • ↑ Caspase-3 activation Mouse, Tat tg; primary OLs (Hauser et al.
T578 7931-7936 Sentence denotes 2009)
T579 7937-7983 Sentence denotes Blood-brain barrier and the neurovascular unit
T580 7984-8046 Sentence denotes BBB model integrity and function Tat1–86 No Morphine • ↑ TNF-α
T581 8047-8055 Sentence denotes • ↑ IL-8
T582 8056-8063 Sentence denotes • ↓TEER
T583 8064-8084 Sentence denotes • ↑ JAM-2 expression
T584 8085-8188 Sentence denotes • ↑ Monocyte transmigration with CCL5 Human, using primary BMVEC and primary astrocytes (Mahajan et al.
T585 8189-8194 Sentence denotes 2008)
T586 8195-8223 Sentence denotes ARV accumulation Tat1–86 DTG
T587 8224-8227 Sentence denotes FTC
T588 8228-8317 Sentence denotes TFV Morphine • ↓ Intracellular ARV concentrations Human, primary astrocytes (Patel et al.
T589 8318-8323 Sentence denotes 2019)
T590 8324-8348 Sentence denotes HIV-1 strain differences
T591 8349-8445 Sentence denotes Neuronal Survival Tat1–86 (clades B & C) No Morphine • ↓ Neuronal survival via MOR on mixed glia
T592 8446-8467 Sentence denotes • ↑ ROS in astrocytes
T593 8468-8559 Sentence denotes • ↑ Iba1 and 3-NT microglia with morphine Mouse, primary neurons and mixed glia (Zou et al.
T594 8560-8565 Sentence denotes 2011)
T595 8566-8577 Sentence denotes • gp120IIIB
T596 8578-8592 Sentence denotes • gp120MN (X4)
T597 8593-8816 Sentence denotes • gp120ADA (R5) No Morphine ↓ Neuronal survival in presence of glia with gp120MN and transiently with gp120IIIB (X4), not R5-tropic gp120, in combination with morphine Mouse, primary neurons and mixed glia (Podhaizer et al.
T598 8817-8822 Sentence denotes 2012)
T599 8823-8916 Sentence denotes Proliferation and maturational fate of neural progenitors and oligodendroglia • HIVSF162 (R5)
T600 8917-9019 Sentence denotes • HIVIIIB (X4) No Morphine • ↓ Proliferation of immature neural and OL progenitors with Tat + morphine
T601 9020-9071 Sentence denotes • ↓ NPC DNA synthesis with R5-tropic HIV + morphine
T602 9072-9192 Sentence denotes • ↑ NPC DNA synthesis with X4-tropic HIV + morphine Mouse, Tat tg; Mouse, Human, primary neural progenitors (Hahn et al.
T603 9193-9198 Sentence denotes 2012)
T604 9199-9226 Sentence denotes GABA function • HIVBaL (R5)
T605 9227-9254 Sentence denotes • gp120 (ADA, MN, and IIIB)
T606 9255-9317 Sentence denotes • Tat1–86 No Morphine • Tat or morphine ↓ KCC2 levels via CCR5
T607 9318-9447 Sentence denotes • ↑ KCC2 prevents Tat and R5 HIV, gp120, but not X4, gp120 neurotoxicity ± morphine Human, primary neurons, hNPCs (Barbour et al.
T608 9448-9453 Sentence denotes 2020)
T609 9454-9506 Sentence denotes Astroglial CCL5 and neuroprotection • gp120IIIB (X4)
T610 9507-9544 Sentence denotes • gp120BaL (R5) No • Morphine (10 μM)
T611 9545-9613 Sentence denotes • DAMGO • Morphine ↑ astroglial CCL5 blocking gp120BaL neurotoxicity
T612 9614-9765 Sentence denotes • Morphine (or CXCL12) does not block gp120IIIB neurotoxicity Rat, mixed neurons and glia; isolated neurons, astrocytes and microglia (Avdoshina et al.
T613 9766-9771 Sentence denotes 2010)
T614 9772-9865 Sentence denotes aassumed Clade B, unless noted otherwise, b statistical findings for some results are unclear
T615 9866-10776 Sentence denotes ARV, antiretroviral(s); BMVEC, brain vascular endothelial cells; [Ca2+]i intracellular calcium concentration; 8-CAC, 8-carboxamidocyclazocine; DAMGO, D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DCF, dihydro-dichlorofluorescein; DOR, δ-opioid receptor; DHE, dihydroethidium; DTG, dolutegravir; DPDPE, [D-Pen2,D-Pen5]enkephalin; FTC, emtricitabine; GABA, γ-aminobutyric acid; Iba1, ionized calcium-binding adapter molecule 1; JAM-1, junctional adhesion molecule-1; KCC2, K+-Cl− cotransporter 2; KOR, κ-opioid receptor; LTR, long terminal repeat; ΔΨm, mitochondrial inner membrane potential; MOR, μ-opioid receptor; [Na+]i, intracellular sodium concentration; nor-BNI, nor-binaltorphimine; NPCs, neural progenitor cells; OLs, oligodendroglia; ROS, reactive oxygen species; TEER, transendothelial electrical resistance; TFV, tenofovir; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; ZDV, zidovudine
T616 10777-10926 Sentence denotes For practicality, the table is limited to key studies in the CNS with emphasis on neuropathological or neuroimmune rather than psychosocial outcomes.
T617 10927-11334 Sentence denotes With deference toward the excellent studies we excluded: (1) on opioid and HIV effects on PBMCs, or on isolated lymphocytes and monocytes, not directly related to the central nervous system or BBB; (2) on HIV or opioid and ARV interactions in the peripheral nervous system; and (3) studies not directly examining opioid-HIV interactions (irrespective of whether a positive or negative interaction was found)
T618 11336-11385 Sentence denotes Opioid and HIV Interactive Pathology in Astroglia
T619 11386-11480 Sentence denotes Although the extent to which astroglia display productive infection is debated (Russell et al.
T620 11481-11496 Sentence denotes 2017; Ko et al.
T621 11497-11603 Sentence denotes 2019), there is nevertheless considerable evidence of proviral integration in the CNS of PWH (Gorry et al.
T622 11604-11626 Sentence denotes 2003; Churchill et al.
T623 11627-11674 Sentence denotes 2009), infectious animal models (Eugenin et al.
T624 11675-11738 Sentence denotes 2011), and/or cultured human fetal astrocytes (Tornatore et al.
T625 11739-11755 Sentence denotes 1994; Liu et al.
T626 11756-11771 Sentence denotes 2004; Do et al.
T627 11772-11795 Sentence denotes 2014; Narasipura et al.
T628 11796-11811 Sentence denotes 2014; Li et al.
T629 11812-11838 Sentence denotes 2015; Nath 2015; Li et al.
T630 11839-11845 Sentence denotes 2020).
T631 11846-11983 Sentence denotes Integrated HIV sequences have been identified in astrocytes in HIV-infected CNS tissue by laser capture microdissection (Churchill et al.
T632 11984-11990 Sentence denotes 2006).
T633 11991-12149 Sentence denotes Astroglia appear to infect via non-classical, CD4-independent mechanisms, that can have the appearance of virologic synapses, adding to the debate (Liu et al.
T634 12150-12165 Sentence denotes 2004; Do et al.
T635 12166-12181 Sentence denotes 2014; Li et al.
T636 12182-12215 Sentence denotes 2015; Nath 2015; Al-Harthi et al.
T637 12216-12231 Sentence denotes 2019; Li et al.
T638 12232-12238 Sentence denotes 2020).
T639 12239-12485 Sentence denotes Irrespective of whether they become infected, MOR-expressing, HIV or HIV protein-exposed astrocytes release greater amounts of inflammatory cytokines and dysfunction sufficient to harm bystander neurons upon treatment with opiates (El-Hage et al.
T640 12486-12509 Sentence denotes 2005, 2008b; Zou et al.
T641 12510-12530 Sentence denotes 2011; El-Hage et al.
T642 12531-12537 Sentence denotes 2014).
T643 12538-12694 Sentence denotes MOR-expressing subsets of glia, especially microglia and astroglia, are prominent in driving the interactive opioid and HIV neuropathogenesis (Hauser et al.
T644 12695-12740 Sentence denotes 2007, 2012; Hauser and Knapp 2014; Liu et al.
T645 12741-12763 Sentence denotes 2016a; Chilunda et al.
T646 12764-12783 Sentence denotes 2019; Murphy et al.
T647 12784-12790 Sentence denotes 2019).
T648 12791-12951 Sentence denotes When MOR is deleted from glia (astrocytes and microglia), morphine no longer increases the death of Tat-exposed striatal medium spiny neurons (MSNs) (Zou et al.
T649 12952-12958 Sentence denotes 2011).
T650 12959-13070 Sentence denotes Conversely, if MOR is deleted from MSNs, morphine exacerbates the neurotoxic effects of Tat in MSNs (Zou et al.
T651 13071-13077 Sentence denotes 2011).
T652 13078-13236 Sentence denotes The proinflammatory effects of Tat alone or in combination with morphine on glia are mediated through a Beclin-1-dependent autophagy pathway (Rodriguez et al.
T653 13237-13258 Sentence denotes 2017; Lapierre et al.
T654 13259-13265 Sentence denotes 2018).
T655 13266-13499 Sentence denotes Drugs with selective glial anti-inflammatory activity (i.e., ibudilast or AV411) attenuated the deleterious effects of HIV and opiate exposure, including HIV-1 replication, cytokine release, and neurotoxicity in vitro (El-Hage et al.
T656 13500-13506 Sentence denotes 2014).
T657 13507-13595 Sentence denotes Thus, the observed neuronal death is largely mediated by MOR-expressing glia (Zou et al.
T658 13596-13638 Sentence denotes 2011), including astroglia (El-Hage et al.
T659 13639-13689 Sentence denotes 2005, 2008b) and microglia (Turchan-Cholewo et al.
T660 13690-13710 Sentence denotes 2008; Bokhari et al.
T661 13711-13739 Sentence denotes 2009; Turchan-Cholewo et al.
T662 13740-13758 Sentence denotes 2009; Gupta et al.
T663 13759-13765 Sentence denotes 2010).
T664 13766-13901 Sentence denotes The direct contributions of astrocytes to opioid and HIV interactions have been discussed previously (Dutta and Roy 2012; Hauser et al.
T665 13902-13920 Sentence denotes 2012; Reddy et al.
T666 13921-13950 Sentence denotes 2012; Hauser and Knapp 2014).
T667 13951-14048 Sentence denotes Subsets of astroglia can express MOR, DOR and KOR (Stiene-Martin and Hauser 1991; Eriksson et al.
T668 14049-14069 Sentence denotes 1992; Ruzicka et al.
T669 14070-14090 Sentence denotes 1995; Gurwell et al.
T670 14091-14110 Sentence denotes 1996; Hauser et al.
T671 14111-14132 Sentence denotes 1996; Peterson et al.
T672 14133-14159 Sentence denotes 1998; Stiene-Martin et al.
T673 14160-14225 Sentence denotes 1998, 2001), as well as endogenous opioid peptides (Vilijn et al.
T674 14226-14246 Sentence denotes 1988; Shinoda et al.
T675 14247-14266 Sentence denotes 1989; Spruce et al.
T676 14267-14286 Sentence denotes 1990; Hauser et al.
T677 14287-14303 Sentence denotes 1990; Low et al.
T678 14304-14310 Sentence denotes 1992).
T679 14311-14494 Sentence denotes It appears that the ‘early’ events triggering the release of proinflammatory cytokines (i.e., TNF-α and IL-1β) from astroglia can be mediated by HIV Tat exposure alone (El-Hage et al.
T680 14495-14518 Sentence denotes 2005, 2006a, b, 2008a).
T681 14519-14800 Sentence denotes Opioids enhance HIV-1-induced inflammation later during the inflammatory cascade by exacerbating the sustained release of CCL5 from astrocytes, which subsequently triggers the release of CCL2 thereby enhancing the recruitment and activation of macrophages/microglia (El-Hage et al.
T682 14801-14817 Sentence denotes 2008a) (Fig. 1).
T683 14818-14974 Sentence denotes This is caused by the morphine-dependent exacerbation of Tat-induced increases in intracellular calcium concentration ([Ca2+]i) in astroglia (El-Hage et al.
T684 14975-15138 Sentence denotes 2005), which accelerates the trafficking of NF-κB p65 (RelA) subunits to the nucleus and sustained CCL2, CCL5, and IL-6 transcription in astrocytes (El-Hage et al.
T685 15139-15146 Sentence denotes 2008b).
T686 15147-15350 Sentence denotes Fig. 1 Opioids exacerbate HIV-1-induced CNS inflammation, in part, by augmenting CCL5-dependent increases in CCL2—key sites of opioid-HIV convergent interactions in glial inflammatory signaling cascades.
T687 15351-15625 Sentence denotes Subpopulations of striatal glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in wildtype mice normally express CCR2 immunoreactivity (a-b; arrows), CCL2 (c; arrow), or μ-opioid receptor (MOR) (d; arrows) immunoreactivity (scale bars a-b = 25 μm; c-d = 15 μm).
T688 15626-15906 Sentence denotes CCR2 deletion (−/−) significantly reduces HIV-1 Tat ± morphine-induced increases in GFAP+ astroglia (e) and F4/80+ macrophages/microglia (f) compared to wild type (+/+) mice at sites near (300 ± 100 μm) the site of Tat injection (*p < 0.05 vs. wild type mice) (see, El-Hage et al.
T689 15907-15914 Sentence denotes 2006a).
T690 15915-16463 Sentence denotes In wild-type mice, Tat ± morphine administration markedly increases the proportion of CCL2 immunoreactive astrocytes (g) or macrophages/microglia (h) [*p < 0.05 vs. other groups in wild-type or CCL5(−/−) mice; bp < 0.05 vs. vehicle- or Tat plus morphine-treated wild-type mice; #p < 0.05 vs. equivalent treatment in wild-type mice], while in CCL5 null mice, significant increases in CCL2 immunoreactivity were only seen in macrophages/microglia co-exposed to Tat and morphine (§p < 0.05 vs. vehicle injected CCL5 knockout mice) (see, El-Hage et al.
T691 16464-16471 Sentence denotes 2008a).
T692 16472-16644 Sentence denotes CCL5 expression in striatal GFAP-immunoreactive astrocytes (arrows) increases following Tat injections (i, j) compared to wild-type control mice (not shown) (El-Hage et al.
T693 16645-16652 Sentence denotes 2008a).
T694 16653-16905 Sentence denotes Opioids exacerbate HIV-1-induced CNS inflammation, in part, by increasing CCL5 and augmenting CCR5-dependent increases in CCL2 production by astrocytes resulting in the activation and recruitment of microglia/macrophages and spiraling inflammation (k).
T695 16906-17011 Sentence denotes Additional factors likely mediate the proinflammatory cascade, but these are less well substantiated (?).
T696 17012-17427 Sentence denotes Moreover, autocrine and reciprocal paracrine (astroglial ↔ macrophage/microglial) intercellular, feedback amplification mechanisms from macrophages/microglia are likely to be operative (dashed red arrow) (also see, Kang and Hebert 2011) and occur elsewhere within the cascade (not shown); effects of HIV-1 Tat/HIV, red arrows; sites of opioid convergence, blue arrows; pro-BDNF:mature BDNF (mBDNF) ratio (Kim et al.
T697 17428-17581 Sentence denotes 2018). (a-f) Modified and reprinted with permission from El-Hage et al. (2006a). (g-k) Modified and reprinted with permission from El-Hage et al. (2008a)
T698 17583-17632 Sentence denotes Opioid and HIV Interactive Pathology in Microglia
T699 17633-17744 Sentence denotes Unlike in astrocytes, opiate and HIV interactions in microglia tend to be self-limiting (Turchan-Cholewo et al.
T700 17745-17751 Sentence denotes 2009).
T701 17752-17936 Sentence denotes Opiates initially trigger large increases in the production of proinflammatory cytokines (Hauser, unpublished), reactive oxygen (ROS) and nitrogen (RNS) species (Turchan-Cholewo et al.
T702 17937-17986 Sentence denotes 2009), and the release of glutamate (Gupta et al.
T703 17987-18068 Sentence denotes 2010) and ATP (Sorrell and Hauser 2014) extracellularly in Tat-exposed microglia.
T704 18069-18190 Sentence denotes The release of glutamate is mediated by the catalytic subunit of the cystine-glutamate antiporter xc− (xCT) (Gupta et al.
T705 18191-18197 Sentence denotes 2010).
T706 18198-18437 Sentence denotes Interestingly, following acute increases in the release of cytokines (e.g., TNF-α; unpublished), morphine no longer increases Tat-induced cytokine levels at 24 h; instead, their levels are reduced by opiate-dependent proteasome inhibition.
T707 18438-18667 Sentence denotes The proteasome inhibitor, MG115, mimics the effects of morphine in decreasing proteasome activity at 24 h and blocks TNFα, IL-6, and CCL2 release from microglia, but does not increase ROS or RNS production (Turchan-Cholewo et al.
T708 18668-18674 Sentence denotes 2009).
T709 18675-18841 Sentence denotes The ubiquitin proteasome system (UPS) is typically viewed as contributing to opiate tolerance and physical dependence by modulating MOR downregulation (Massaly et al.
T710 18842-18861 Sentence denotes 2014; Caputi et al.
T711 18862-18915 Sentence denotes 2019), rather than MOR activity constraining the UPS.
T712 18916-19263 Sentence denotes Thus, while HIV-exposed, MOR-expressing microglia show a burst of ROS and proinflammatory cytokine production in response to morphine, the cytokine release collapses within 24 h seemingly because sustained opiate exposure inhibits the UPS thereby preventing degradation of the IκB subunit and nuclear translocation of NF-κB (Turchan-Cholewo et al.
T713 19264-19270 Sentence denotes 2009).
T714 19271-19476 Sentence denotes While neither astroglia nor microglia alone mimic the full inflammatory profile seen with opiates and HIV in the CNS; in combination, the neuroimmune signature more accurately mimics that seen in neuroHIV.
T715 19477-19677 Sentence denotes Accordingly, we have proposed that opioids promote positive feedback through separate actions in astroglia and microglia in neuroHIV—resulting in spiraling inflammation and cytotoxicity (Hauser et al.
T716 19678-19690 Sentence denotes 2005, 2007).
T717 19692-19739 Sentence denotes Opioid and HIV Interactive Pathology in Neurons
T718 19740-20044 Sentence denotes Besides accentuating HIV-induced neurotoxicity via glial-mediated mechanisms, morphine appears to converge with HIV Tat to dysregulate ion homeostasis and dendritic injury through potential direct actions on neurons, even though some contributions of glia cannot be excluded in this study (Fitting et al.
T719 20045-20052 Sentence denotes 2014a).
T720 20053-20374 Sentence denotes Combined morphine and Tat exposure accelerates the formation of Tat-induced focal dendritic varicosities/swelling via a MOR-related mechanism that was caused by focal increases in Na+ influx and [Ca2+]i, an overload of Na+/K+-ATPase, ATP depletion, and a collapse in mitochondrial inner membrane potential (Fitting et al.
T721 20375-20382 Sentence denotes 2014a).
T722 20383-20601 Sentence denotes Importantly, morphine’s additive effects were mediated via a MOR-related mechanism, as the exacerbating effects of morphine were absent in neurons from MOR knockout mice, thus excluding TLR4 involvement (Fitting et al.
T723 20602-20609 Sentence denotes 2014a).
T724 20610-20766 Sentence denotes Further, morphine exacerbated Tat-dependent focal losses in ion homeostasis by mobilizing [Ca2+]i through ryanodine-2 (RyR2)-sensitive sites (Fitting et al.
T725 20767-20783 Sentence denotes 2014a) (Fig. 2).
T726 20784-20891 Sentence denotes Although morphine typically acts via MOR in an inhibitory manner by activating Gi/o-proteins (Sharma et al.
T727 20892-20911 Sentence denotes 1977; Moises et al.
T728 20912-21025 Sentence denotes 1994; Al-Hasani and Bruchas 2011), MOR-dependent stimulation of PI3-kinase and Ca2+ mobilization (Leopoldt et al.
T729 21026-21086 Sentence denotes 1998) in neurons via the Gβγ protein subunit (Mathews et al.
T730 21087-21129 Sentence denotes 2008) is presumed operative here (Fig. 2).
T731 21130-21427 Sentence denotes Fig. 2 Morphine exacerbates the excitotoxic effects of HIV Tat by mobilizing Ca2+ from ryanodine (RyR)-sensitive internal stores. (a) Tat-induced increases in [Ca2+]i were not attenuated by ryanodine, whereas ryanodine and pyruvate attenuate combined Tat and morphine-induced increases in [Ca2+]i.
T732 21428-21780 Sentence denotes Nimodipine (L-type Ca2+ channel blocker) and dantrolene did not show any effects. (b) Average [Ca2+]i over 10 min indicated ryanodine significantly blocked combined Tat and morphine-induced increases in [Ca2+]i, whereas no effects were noted for nimodipine, dantrolene, or pyruvate. *p < 0.05 vs. control, #p < 0.05 vs. Tat 50 nM, §p < 0.05 vs. TM, TM:
T733 21781-21909 Sentence denotes Tat 50 nM + Morphine 500 nM. (c) Summary of HIV-1 Tat and morphine interactive neuronal injury in striatal medium spiny neurons.
T734 21910-22355 Sentence denotes Combined Tat and morphine promotes structural and functional defects in dendrites via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), N-methyl-D-aspartic acid receptors (NMDAR), and MOR, causing influxes of Na+ and/or Ca2+, compensatory increases in Na+/K+-dependent ATPase activity, and a rapid loss in ATP mobilization with an inability to extrude excess Na+ via Na+/K+-ATPase caused by mitochondrial hyperpolarization.
T735 22356-22787 Sentence denotes Dysregulation of [Ca2+]i homeostasis by combined Tat and morphine appears to be mediated downstream of [Na+]i at the level of calcium mobilization, which in turn appears to be regulated via ryanodine (RyR)-sensitive sites, and enhanced by morphine exposure likely via MOR-dependent stimulation of PI3-kinase and Ca2+ mobilization via the Gβγ protein subunit. (a-b) Modified and reprinted with permission from Fitting et al. (2014a)
T736 22788-22840 Sentence denotes Glial-derived neuronal injury is not unidirectional.
T737 22841-23039 Sentence denotes Neuronal damage-associated molecular patterns (DAMPs) and dysfunction can trigger both infected and uninfected glia to become reactive, resulting in further neuronal damage and escalating pathology.
T738 23040-23131 Sentence denotes Neuronal injury can reactivate HIV in latently infected microglia (Alvarez-Carbonell et al.
T739 23132-23138 Sentence denotes 2019).
T740 23139-23597 Sentence denotes While the events underlying the disruption of neuronal-microglial activation that trigger the emergence of latent HIV are unclear, the induction of HIV expression appears to involve the production of DAMPs by injured neurons and can be turned “on”, e.g., by methamphetamine-induced sigma-1 (σ1) receptor activation, TNF-α and IL-1β, and TLR3 activation can be turned “off” by CX3CL1/fractalkine or glucocorticoid receptor activation (Alvarez-Carbonell et al.
T741 23598-23610 Sentence denotes 2017, 2019).