Abstract
HIV-associated neurocognitive disorder (HAND) is a common complication of HIV infection, whose development is known to be facilitated by inflammation and exacerbated by morphine. Previously, using the gp120 transgenic (tg) mouse model in combination with LP-BM5 (a murine retrovirus that can cause systemic immunodeficiency in susceptible mouse strains) we demonstrated differential gp120-associated central nervous system (CNS) neuroinflammatory responses under immunocompetent (-LP-BM5) vs. immunocompromised (+LP-BM5) conditions. Here, we further investigated the effects of morphine on gp120-associated neuroinflammatory response within the hippocampus under differential immune status. First, we confirmed that morphine treatment (2 × 25 mg pellets) did not significantly affect the development of immunodeficiency induced by LP-BM5 and all brain regions examined (hippocampus, striatum, and frontal lobe) had detectable LP-BM5 viral gag genes. Morphine notably reduced the performance of gp120tg+ mice in the alteration T-maze assay when 2-minute retention was used, regardless of LP-BM5 treatment. Morphine further enhanced GFAP expression in gp120tg+ mice regardless of host immune status, while promoted CD11b expression only in immunocompetent mice, regardless of gp120tg expression. In immunocompetent gp120tg+ mice, morphine increased the RNA expression of CCL2, CCL5, CXCL10, IL-12p40, and IFNβ; while under the immunodeficient condition, morphine downregulated the expression of CCL2, CCL5, CXCL10, IL-12p40, and IL-1β. Further, expression of TNFα and IFNγ were enhanced by morphine regardless of host immune status. Altogether, our results suggest that the effects of morphine are complex and dependent on the immune status of the host, and host immune status-specific, targeted anti-neuroinflammatory strategies are required for effective treatment of HAND.
Graphic Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Acchioni C, Marsili G, Perrotti E, Remoli AL, Sgarbanti M, Battistini A (2015) Type I IFN--a blunt spear in fighting HIV-1 infection Cytokine & growth factor reviews. 26:143–158. https://doi.org/10.1016/j.cytogfr.2014.10.004
Anthony IC, Arango JC, Stephens B, Simmonds P, Bell JE (2008) The effects of illicit drugs on the HIV infected brain. Front Biosci 13:1294–1307. https://doi.org/10.2741/2762
Arabatzis TJ, Wakley AA, McLane VD, Canonico D, Cao L (2020) Effects of HIV gp120 on Neuroinflammation in Immunodeficient vs. Immunocompetent States Journal of neuroimmune pharmacology: the official journal of the Society on NeuroImmune Pharmacology. https://doi.org/10.1007/s11481-020-09936-5
Asensio VC et al (2001) Interferon-Independent, Human Immunodeficiency Virus Type 1 gp120-Mediated Induction of CXCL10/IP-10 Gene Expression by Astrocytes In Vivo and In Vitro. J Virol 75:7067–7077. https://doi.org/10.1128/jvi.75.15.7067-7077.2001
Bandaru VV, Patel N, Ewaleifoh O, Haughey NJ (2011) A failure to normalize biochemical and metabolic insults during morphine withdrawal disrupts synaptic repair in mice transgenic for HIV-gp120. Journal of neuroimmune pharmacology: the official journal of the Society on NeuroImmune Pharmacology 6:640–649. https://doi.org/10.1007/s11481-011-9289-0
Bell JE, Brettle RP, Chiswick A, Simmonds P (1998) HIV encephalitis, proviral load and dementia in drug users and homosexuals with AIDS. Effect of neocortical involvement Brain 121. 2043–2052. https://doi.org/10.1093/brain/121.11.2043. Pt 11
Beltran JA, Pallur A, Chang SL (2006) HIV-1 gp120 up-regulation of the mu opioid receptor in TPA-differentiated HL-60 cells. Int Immunopharmacol 6:1459–1467. https://doi.org/10.1016/j.intimp.2006.04.018
Bernstein MA, Welch SP (1998) mu-Opioid receptor down-regulation and cAMP-dependent protein kinase phosphorylation in a mouse model of chronic morphine tolerance. Brain research Molecular brain research 55:237–242. https://doi.org/10.1016/s0169-328x(98)00005-9
Brabers NACH, Nottet HSLM (2006) Role of the pro-inflammatory cytokines TNF-α and IL-1β in HIV-associated dementia European. Journal of Clinical Investigation 36:447–458. https://doi.org/10.1111/j.1365-2362.2006.01657.x
Bradley H et al (2014) Vital Signs: HIV diagnosis, care, and treatment among persons living with HIV--United States, 2011. MMWR Morb Mortal Wkly Rep 63:1113–1117
Burlacu R et al (2019) Plasma CXCL10 correlates with HAND in HIV-infected women. J Neurovirol. https://doi.org/10.1007/s13365-019-00785-4
Cadet P, Weeks BS, Bilfinger TV, Mantione KJ, Casares F, Stefano GB (2001) HIV gp120 and morphine alter µ opiate receptor expression in human vascular endothelium. Int J Mol Med 8:165–169. https://doi.org/10.3892/ijmm.8.2.165
Cao L, Butler MB, Tan L, Draleau KS, Koh WY (2012) Murine immunodeficiency virus-induced peripheral neuropathy and the associated cytokine responses. J Immunol 189:3724–3733. https://doi.org/10.4049/jimmunol.1201313
Chen SH, Chen SS, Wang YP, Chen LK (2019) Effects of systemic and neuraxial morphine on the. immune system Medicine 98:e15375. https://doi.org/10.1097/md.0000000000015375
Christophi GP, Hudson CA, Panos M, Gruber RC, Massa PT (2009) Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease. J Virol 83:522–539. https://doi.org/10.1128/jvi.01210-08
Cook WJ, Green KA, Obar JJ, Green WR (2003) Quantitative analysis of LP-BM5 murine leukemia retrovirus RNA using real-time RT-PCR. J Virol Methods 108:49–58. https://doi.org/10.1016/S0166-0934(02)00256-2
D’Hooge R, Franck F, Mucke L, De Deyn PP (1999) Age-related behavioural deficits in transgenic mice expressing the HIV-1 coat protein gp120 European. J Neurosci 11:4398–4402. https://doi.org/10.1046/j.1460-9568.1999.00857.x
Deacon RM, Rawlins JN (2006) T-maze alternation in the rodent. Nat Protoc 1:7–12. https://doi.org/10.1038/nprot.2006.2
Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29:313–326. https://doi.org/10.1089/jir.2008.0027
Eisenstein TK (2019) The Role of Opioid Receptors in Immune System. Function Front Immunol 10:2904. https://doi.org/10.3389/fimmu.2019.02904
Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44. https://doi.org/10.1038/nrn2040
Giese NA, Giese T, Morse HC (1994) Murine AIDS is an antigen-driven disease: requirements for major histocompatibility complex class II expression and CD4+ T cells. J Virol 68:5819–5824
Gonzalez E et al (2002) HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci U S A 99:13795–13800. https://doi.org/10.1073/pnas.202357499
Hauser KF, Knapp PE (2014) Interactions of HIV and drugs of abuse: the importance of glia, neural progenitors, and host genetic factors. Int Rev Neurobiol 118:231–313. https://doi.org/10.1016/B978-0-12-801284-0.00009-9
Heaton RK et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy. CHARTER Study Neurology 75:2087–2096. https://doi.org/10.1212/WNL.0b013e318200d727
Iqbal O’Meara, Miller Ferguson AM, Zven N, Karam SE, Meyer OL, Bigbee LC, Sato-Bigbee JW C (2020) Potential Neurodevelopmental Effects of Pediatric Intensive Care Sedation and Analgesia: Repetitive Benzodiazepine and Opioid Exposure Alters Expression of Glial and Synaptic Proteins in Juvenile Rats. Critical care explorations 2:e0105. https://doi.org/10.1097/cce.0000000000000105
Kelder W, McArthur JC, Nance-Sproson T, McClernon D, Griffin DE (1998) β-Chemokines MCP-1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus–associated dementia. Ann Neurol 44:831–835. https://doi.org/10.1002/ana.410440521
Kelly CM et al (2014) HIV associated neurocognitive disorders (HAND) in Malawian adults and effect on adherence to combination anti-retroviral therapy: a cross sectional study. PLoS One 9:e98962. https://doi.org/10.1371/journal.pone.0098962
Kundu K, Dutta K, Nazmi A, Basu A (2013) Japanese encephalitis virus infection modulates the expression of suppressors of cytokine signaling (SOCS) in macrophages: Implications for the hosts’ innate immune response. Cell Immunol 285:100–110. https://doi.org/10.1016/j.cellimm.2013.09.005
Kustova Y, Grinberg A, Basile AS (1999) Increased blood-brain barrier permeability in LP-BM5 infected mice is mediated by neuroexcitatory mechanisms. Brain Res 839:153–163. https://doi.org/10.1016/s0006-8993(99)01734-5
Lalonde R (2002) The neurobiological basis of spontaneous alternation Neurosci. Biobehav Rev 26:91–104. https://doi.org/10.1016/s0149-7634(01)00041-0
Lee I, Kesner RP (2003) Time-Dependent Relationship between the Dorsal Hippocampus and the Prefrontal Cortex in Spatial Memory. The Journal of Neuroscience 23:1517–1523. https://doi.org/10.1523/jneurosci.23-04-01517.2003
Lee S, Chung Y-S, Yoon C-H, Shin Y, Kim S, Choi B-S, Kim SS (2015) Interferon-inducible protein 10 (IP-10) is associated with viremia of early HIV-1 infection in Korean patients. J Med Virol 87:782–789. https://doi.org/10.1002/jmv.24026
Letendre SL, Ellis RJ, Everall I, Ances B, Bharti A, McCutchan JA (2009) Neurologic complications of HIV disease and their treatment Top. HIV Med 17:46–56
Li W, Green WR (2006) The Role of CD4 T Cells in the Pathogenesis of Murine AIDS. J Virol 80:5777–5789. https://doi.org/10.1128/jvi.02711-05
Lu Y et al (2014) Differential Pro-Inflammatory Responses of Astrocytes and Microglia Involve STAT3 Activation in Response to 1800 MHz. Radiofrequency Fields PloS One 9:e108318. https://doi.org/10.1371/journal.pone.0108318
Maartens G, Celum C, Lewin SR (2014) HIV infection: epidemiology, pathogenesis, treatment, and prevention. The Lancet 384:258–271. https://doi.org/10.1016/S0140-6736(14)60164-1
Mahajan SD, Aalinkeel R, Reynolds JL, Nair BB, Fernandez SF, Schwartz SA, Nair MP (2005) Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells. Curr HIV Res 3:277–288. https://doi.org/10.2174/1570162054368048
Mateu-Gelabert P, Guarino H, Jessell L, Teper A (2015) Injection and sexual HIV/HCV risk behaviors associated with nonmedical use of prescription opioids among young adults in New York. City Journal of substance abuse treatment 48:13–20. https://doi.org/10.1016/j.jsat.2014.07.002
Maung R et al (2014) CCR5 Knockout Prevents Neuronal Injury and Behavioral Impairment Induced in a Transgenic Mouse Model by a CXCR4-Using HIV-1 Glycoprotein 120. J Immunol 193:1895–1910. https://doi.org/10.4049/jimmunol.1302915
McArthur JC (2004) HIV dementia: an evolving disease. J Neuroimmunol 157:3–10. https://doi.org/10.1016/j.jneuroim.2004.08.042
McArthur JC, Steiner J, Sacktor N, Nath A (2010) Human immunodeficiency virus-associated neurocognitive disorders. Mind the gap Annals of Neurology 67:699–714. https://doi.org/10.1002/ana.22053
McLane VD, Cao L, Willis CL (2014) Morphine increases hippocampal viral load and suppresses frontal lobe CCL5 expression in the LP-BM5 AIDS model. J Neuroimmunol 269:44–51. https://doi.org/10.1016/j.jneuroim.2014.02.010
McLane VD, Bergquist I, Cormier J, Barlow DJ, Houseknecht KL, Bilsky EJ, Cao L (2017) Long-term morphine delivery via slow release morphine pellets or osmotic pumps: Plasma concentration, analgesia, and naloxone-precipitated withdrawal Life sciences. 185:1–7. https://doi.org/10.1016/j.lfs.2017.07.016
McLane VD, Kumar S, Leeming R, Rau S, Willis CL, Cao L (2018) Morphine-potentiated cognitive deficits correlate to suppressed hippocampal iNOS RNA expression and an absent type 1 interferon response in LP-BM5 murine AIDS. J Neuroimmunol 319:117–129. https://doi.org/10.1016/j.jneuroim.2018.02.017
Mimiaga MJ et al (2013) Substance use among HIV-infected patients engaged in primary care in the United States: findings from the Centers for AIDS Research Network of Integrated Clinical Systems cohort American. J Public Health 103:1457–1467. https://doi.org/10.2105/ajph.2012.301162
Morse HC 3rd, Chattopadhyay SK, Makino M, Fredrickson TN, Hügin AW, Hartley JW (1992) Retrovirus-induced immunodeficiency in the mouse: MAIDS as a model for AIDS AIDS. (London, England) 6:607–621. https://doi.org/10.1097/00002030-199207000-00001
Murphy A, Barbaro J, Martínez-Aguado P, Chilunda V, Jaureguiberry-Bravo M, Berman JW (2019) The Effects of Opioids on HIV Neuropathogenesis Frontiers in Immunology. 10. https://doi.org/10.3389/fimmu.2019.02445
Nasi M et al (2017) Ageing and inflammation in patients with HIV infection. Clin Exp Immunol 187:44–52. https://doi.org/10.1111/cei.12814
Nath A et al (2002) Molecular basis for interactions of HIV and drugs of abuse. J Acquir Immune Defic Syndr 31(Suppl 2):S62–69. https://doi.org/10.1097/00126334-200210012-00006
Perrot S, Guilbaud G, Kayser V (2001) Differential Behavioral Effects of Peripheral and Systemic Morphine and Naloxone in a Rat Model of Repeated. Acute Inflammation Anesthesiology 94:870–875. https://doi.org/10.1097/00000542-200105000-00027
Peters PJ et al (2016) HIV Infection Linked to Injection Use of Oxymorphone in Indiana, 2014-2015 The New England. J Med 375:229–239. https://doi.org/10.1056/NEJMoa1515195
Ploquin MJ et al (2016) Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease. Onset PLoS Pathog 12:e1005774. https://doi.org/10.1371/journal.ppat.1005774
Podhaizer EM, Zou S, Fitting S, Samano KL, El-Hage N, Knapp PE, Hauser KF (2012) Morphine and gp120 toxic interactions in striatal neurons are dependent on HIV-1 strain. Journal of neuroimmune pharmacology: the official journal of the Society on NeuroImmune Pharmacology 7:877–891. https://doi.org/10.1007/s11481-011-9326-z
Raehal KM, Bohn LM (2005) Mu opioid receptor regulation and opiate responsiveness. AAPS J 7:E587–E591. https://doi.org/10.1208/aapsj070360
Reddy PV, Pilakka-Kanthikeel S, Saxena SK, Saiyed Z, Nair MP (2012) Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder AIDS research and treatment 2012. 953678. https://doi.org/10.1155/2012/953678
Robertson KR et al (2007) The prevalence and incidence of neurocognitive impairment in the HAART era AIDS. (London, England) 21:1915–1921. https://doi.org/10.1097/QAD.0b013e32828e4e27
Ronaldson PT, Bendayan R (2006) HIV-1 viral envelope glycoprotein gp120 triggers an inflammatory response in cultured rat astrocytes and regulates the functional expression of P-glycoprotein. Mol Pharmacol 70:1087–1098. https://doi.org/10.1124/mol.106.025973
Sacktor N (2018) Changing clinical phenotypes of HIV-associated neurocognitive disorders. J Neurovirol 24:141–145. https://doi.org/10.1007/s13365-017-0556-6
Saylor D et al (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234–248. https://doi.org/10.1038/nrneurol.2016.27
Sei Y, Kustova Y, Li Y, Morse HC 3, Skolnick P, Basile AS (1998) The encephalopathy associated with murine acquired immunodeficiency syndrome Annals of the New York. Academy of Sciences 840:822–834. https://doi.org/10.1111/j.1749-6632.1998.tb09620.x
Serrano-Pozo A, Muzikansky A, Gómez-Isla T, Growdon JH, Betensky RA, Frosch MP, Hyman BT (2013) Differential Relationships of Reactive Astrocytes and Microglia to Fibrillar Amyloid Deposits in Alzheimer Disease. Journal of Neuropathology & Experimental Neurology 72:462–471. https://doi.org/10.1097/NEN.0b013e3182933788
Sil S, Periyasamy P, Thangaraj A, Niu F, Chemparathy DT, Buch S (2021) Advances in the Experimental Models of HIV-Associated Neurological Disorders Current HIV/AIDS reports. https://doi.org/10.1007/s11904-021-00570-1
Sivro A, Su RC, Plummer FA, Ball TB (2014) Interferon responses in HIV infection: from protection to disease. AIDS Rev 16:43–51
Spudich S et al (2019) Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance. J Clin Invest 129:3339–3346. https://doi.org/10.1172/JCI127413
Thaney VE, O’Neill AM, Hoefer MM, Maung R, Sanchez AB, Kaul M (2017) IFNβ Protects Neurons from Damage in a Murine Model of HIV-1 Associated. Brain Injury Scientific reports 7:46514. https://doi.org/10.1038/srep46514
Thaney VE, Sanchez AB, Fields JA, Minassian A, Young JW, Maung R, Kaul M (2018) Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS. research J Neurovirol 24:156–167. https://doi.org/10.1007/s13365-017-0584-2
Toggas SM, Masliah E, Rockenstein EM, Rail GF, Abraham CR, Mucke L (1994) Central nervous system damage produced by expression of the HIV-1 coat protein gpl20 in. transgenic mice Nature 367:188–193. https://doi.org/10.1038/367188a0
Turchan-Cholewo J, Dimayuga FO, Ding Q, Keller JN, Hauser KF, Knapp PE, Bruce-Keller AJ (2008) Cell-specific actions of HIV-Tat and morphine on opioid receptor expression in glia. J Neurosci Res 86:2100–2110. https://doi.org/10.1002/jnr.21653
Wang Y, Wang X, Ye L, Li J, Song L, Fulambarkar N, Ho W (2012) Morphine Suppresses IFN Signaling Pathway and Enhances AIDS Virus Infection. PLoS One 7:e31167. https://doi.org/10.1371/journal.pone.0031167
Watanabe D et al (2010) Sustained High Levels of Serum Interferon-γ During HIV-1 Infection: A Specific Trend Different from Other. Cytokines Viral Immunology 23:619–625. https://doi.org/10.1089/vim.2010.0065
Watkins CC, Treisman GJ (2015) Cognitive impairment in patients with AIDS - prevalence and severity HIV AIDS. (Auckl) 7:35–47. https://doi.org/10.2147/HIV.S39665
Wei J, Carroll RJ, Harden KK, Wu G (2012) Comparisons of treatment means when factors do not interact in two-factorial studies. Amino Acids 42:2031–2035. https://doi.org/10.1007/s00726-011-0924-0
Weisberg DF et al (2015) Long-term Prescription of Opioids and/or Benzodiazepines and Mortality Among HIV-Infected and Uninfected Patients. J Acquir Immune Defic Syndr 69:223–233. https://doi.org/10.1097/QAI.0000000000000591
World Health Organization Myanmar (2019) HIV-AIDS, WHO Myanmar World AIDS Day special WHO Myanmar factsheet special. https://cdn.who.int/media/docs/default-source/searo/myanmar/factsheet-hiv-aids-wad-2019.pdf?sfvrsn=ffebd469_0
Yeung MC, Pulliam L, Lau AS (1995) The HIV envelope protein gp120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-alpha AIDS (London. England) 9:137–143
Young AM, Havens JR (2012) Transition from first illicit drug use to first injection drug use among rural Appalachian drug users: a cross-sectional comparison and retrospective survival analysis Addiction. (Abingdon, England) 107:587–596. https://doi.org/10.1111/j.1360-0443.2011.03635.x
Zhao T-z et al (2009) Bovine serum albumin promotes IL-1β and TNF-α secretion by N9 microglial cells. Neurol Sci 30:379–383. https://doi.org/10.1007/s10072-009-0123-x
Acknowledgements
The authors would like to thank Dr. Marcus Kaul from the University of California Riverside, Riverside, CA, USA for kindly providing the HIV gp120tg mice for breeding at our animal facility. We also would like to thank Dr. William Green from the Dartmouth College Geisel School of Medicine, Hanover, NH for providing the original LP-BM5 viral stock. We are also grateful for the statistical help from Dr. Woon Yuen Koh from the Department of Mathematics, College of Arts and Sciences at the University of New England. This work was funded in part by NIH grants NIH/NINDS R01S098426 (PI Cao) and NIH/NIDA R21DA044886 (PI Cao).
Funding
This work was funded by NIH grant NIH/NINDS R01S098426 (PI Cao).
Author information
Authors and Affiliations
Contributions
Ling Cao contributed to the study conception and design, supervised the conduction of the study, and participated in data analysis and manuscript preparation. Dalton Canonico participated in data collection, statistical analysis and manuscript preparation. Sadie Casale and Tristan Look participated in data collection, data input, and reviewed the manuscript.
Corresponding author
Ethics declarations
Conflict of Interest
All authors declare no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Canonico, D., Casale, S., Look, T. et al. Effects of Morphine on Gp120-induced Neuroinflammation Under Immunocompetent Vs. Immunodeficient Conditions. J Neuroimmune Pharmacol 18, 24–40 (2023). https://doi.org/10.1007/s11481-021-10040-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-021-10040-5