Elsevier

Journal of Neuroimmunology

Volume 319, 15 June 2018, Pages 117-129
Journal of Neuroimmunology

Morphine-potentiated cognitive deficits correlate to suppressed hippocampal iNOS RNA expression and an absent type 1 interferon response in LP-BM5 murine AIDS

https://doi.org/10.1016/j.jneuroim.2018.02.017Get rights and content

Highlights

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    Morphine altered viral load and inflammation in the LP-BM5/MAIDS model.

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    Morphine reduced CCL5 expression in hippocampus, striatum, and frontal lobe.

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    Morphine increased viral load in hippocampus, correlating to cognitive impairment.

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    Morphine reduced viral load in the striatum, correlating to increased type 1 IFN.

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    Hippocampus and frontal lobe showed no change in type 1 IFN with LP-BM5 ± morphine.

Abstract

Opioid use accelerates neurocognitive impairment in HIV/AIDS patients. We assessed the effect of chronic morphine treatment and LP-BM5/murine AIDS (MAIDS) infection on cognition, cytokine production, and type 1 interferon (IFN) expression in the murine CNS. Morphine treatment decreased expression of pro-inflammatory factors (CCL5, iNOS) and reduced cognitive performance in LP-BM5-infected mice, correlating to increased hippocampal viral load and a blunted type 1 IFN response. In the striatum, morphine reduced viral load while increasing IFN-α RNA expression. Our results suggest that differentially regulated type 1 IFN responses may contribute to distinct regional outcomes in the hippocampus and striatum in LP-BM5/MAIDS.

Introduction

Nearly half of HIV-1-infected patients exhibit signs of HIV-associated neurocognitive deficits (HAND), despite improved viral control with modern combination antiretroviral therapy (Heaton et al., 2010; Robertson et al., 2007). Heroin, morphine, and other opioids/opiates increase both the risk and severity of HAND (Hauser et al., 2012; Nath et al., 2002; Roy et al., 2011). With nearly one-third of patients reporting opioid abuse, these drugs can significantly impact disease outcomes and quality of life for HIV patients (Bell et al., 1998; UNAIDS, 2013).

Morphine interacts with neurotoxic HIV-1 proteins such as transactivator of transcription (Tat) to modulate the CNS immune response, which is primarily mediated by resident glia (microglia, astrocytes) (Hauser et al., 2012; Roy et al., 2011). Morphine exposure decreased HIV-1-Tat-induced microglial production of pro-inflammatory cytokines TNF-α, IL-6, and CCL2/MCP-1 (Turchan-Cholewo et al., 2009) as well as astrocytic production of IL-8 (Reddy et al., 2012) in vitro. In contrast, morphine significantly increased HIV-1-Tat-induced striatal astrocyte production of TNF-α, IFN-γ, and CCL5/RANTES in vitro (El-Hage et al., 2008, 2005). These effects are likely region-specific: the hippocampus exhibits a more subtle pathology in HIV-Tat transgenic mice than the striatum, including impaired long-term potentiation and reduced dendritic spine density in CA1 pyramidal neurons (Fitting et al., 2013). There is limited data available on how these morphine-induced alterations in glial cytokine expression affect the overall balance between pro- and anti-inflammatory factors in the virally-infected CNS, and how the effects of morphine on inflammation may vary between regions.

The type 1 IFN response induces potent antiviral defenses to reduce viral replication throughout the periphery and CNS. Within the CNS, type 1 IFN ligands (e.g., IFN-α, IFN-β) are primarily produced by microglia and astrocytes (Schneider et al., 2014; Yao et al., 2010). High levels of IFN correlated to reduced simian immunodeficiency virus replication in the initial weeks of infection (Barber et al., 2004; Fraietta et al., 2013) and delayed onset of AIDS-like symptoms in the LP-BM5 murine AIDS (MAIDS) model (Heng et al., 1996). However, both HIV-1 and morphine suppress the type 1 IFN response, thereby accelerating viral replication (Solis et al., 2011; Wang et al., 2012; Wie et al., 2013).

In our previous work, we observed increased viral load in the hippocampus of morphine-treated, LP-BM5-infected mice, correlating to moderately reduced expression of the pro-inflammatory chemokine CCL5/RANTES (McLane et al., 2014). We hypothesized that the change in hippocampal viral load could result from a region-specific morphine-induced suppression of the innate immune response. Here, we investigated the effects of morphine on the CNS innate immune system through analysis of mutually antagonistic pro-/anti-inflammatory markers and the type 1 IFN response. We expanded our work to include the striatum, an area that has been shown to have high vulnerability to morphine/HIV-Tat interactions (Bruce-Keller et al., 2008). We predicted that these regional differences in innate immunity could contribute to the deleterious effects of chronic morphine in the LP-BM5/MAIDS model.

Section snippets

Animals and treatment

Seven-week-old male C57BL/6Ncr mice (5 independent cohorts, n = 4 each, 80 mice total, National Cancer Institute, Frederick, MD, USA) were housed in the University of New England animal facility on a 12-hour light/dark cycle. Mice were provided food and water ad libitum. At 8 wks of age, mice were injected i.p. with 5 × 104 plaque-forming units of LP-BM5 retroviral mixture. As described in McLane et al., 2014, mice received subcutaneous (s.c.) implants of morphine (25 mg) or placebo pellets

Impaired cognitive performance correlated to increased viral load in the hippocampus of morphine-treated, LP-BM5-infected mice

At the behavioral level, chronic morphine treatment reduced cognitive performance on the spontaneous alternation T-maze task in LP-BM5-infected mice (n = 15–16), reducing alternation from 74.6 + 3.8% in non-infected, morphine-treated mice to 60.0 + 4.8% in LP-BM5-infected, morphine-treated mice (F3,51 = 2.842, p = 0.047; NI Mor vs. BM5 Mor, p = 0.019; Fig. 1B). These findings indicate morphine treatment in combination with LP-BM5 infection reduced cognitive performance in LP-BM5/MAIDS mice.

Discussion

Opioid abuse has been shown to accelerate HIV-related damage in multiple regions of the CNS, with sensitive regions including the hippocampus and striatum (Fitting et al., 2014; Hauser et al., 2012; Nath et al., 2002). Spatial learning and motor deficits correlate to HIV-Tat-induced damage to the hippocampus (Fitting et al., 2013; Maragos et al., 2003) and striatum (Bruce-Keller et al., 2008), while deficits in executive function indicate an impact on prefrontal cortex function in

Acknowledgments

We would like to thank Ivy Bergquist of the UNE COBRE Behavioral Core for her assistance with behavioral assays. Morphine pellets were provided by Dr. Edward Bilsky. Confocal imaging was completed with the help of the UNE Microscope Core Facility (NSF 1125672, COBRE Imaging Core).

Funding

This work was supported by NIH 5R21NS066130 (LC), P20GM103643 (IDM, LC & CLW), and the UNE Microscope Core Facility (NSF 1125672).

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    Present address: Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.

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